Bicyclically substituted uracils and the use thereof

ABSTRACT

The present application relates to novel bicyclically substituted uracil derivatives, to processes for preparation thereof, to the use thereof alone or in combinations for treatment and/or prophylaxis of diseases, and to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases.

The present application relates to novel bicyclically substituted uracilderivatives, to processes for preparation thereof, to the use thereofalone or in combinations for treatment and/or prophylaxis of diseases,and to the use thereof for production of medicaments for treatmentand/or prophylaxis of diseases.

Chymase is a chymotrypsin-like serine protease which is stored as amacromolecular complex with heparin proteoglycans in secretory vesiclesof mast cells. After activation of the mast cells, chymase is releasedinto the extracellular matrix and activated.

Activated mast cells play an important role in healing wounds and ininflammation processes, for example fibrosis of wounds, angiogenesis andcardiac remodelling (Miyazaki et al., Pharmacol. Ther. 112 (2006),668-676; Shiota et al., J. Hypertens. 21 (2003), 1823-1825). An increasein the number of mast cells has been observed in the event of heartfailure, myocardial infarction and ischaemia, in human atheroscleroticplaques and in abdominal aortic aneurysms (Kovanen et al., Circulation92 (1995), 1084-1088; Libby and Shi, Circulation 115 (2007), 2555-2558;Bacani and Frishman, Cardiol. Rev. 14 (4) (2006), 187-193).Chymase-positive mast cells can also play an important role in thevascular remodelling of the respiratory pathways in the event of asthmaand chronic obstructive pulmonary disease. An increased number of mastcells has been found in endobronchial biopsies of asthma patients(Zanini et al., J. Allergy Clin. Immunol. 120 (2007), 329-333).Moreover, chymase is suspected of being partly responsible for thegenesis of many renal disorders, such as diabetic nephropathy andpolycystic kidney disease (Huang et al., J. Am. Soc. Nephrol. 14 (7)(2003), 1738-1747; McPherson et al., J. Am. Soc. Nephrol. 15 (2) (2004),493-500).

Chymase is predominantly involved in the production of angiotensin II inthe heart, in the artery wall and in the lung, whereas theangiotensin-converting enzyme is responsible for the formation of thepeptide in the circulation system (Fleming I., Circ. Res. 98 (2006),887-896). In addition, chymase cleaves a number of other substrates ofpathological significance. Chymase leads to degradation of extracellularmatrix proteins, such as fibronectin, procollagen and vitronectin, andto the breakoff of focal adhesions. It brings about activation andrelease of TGFβ from its latent form, which plays an important role inthe genesis of cardiac hypertrophy and cardiac fibrosis. The enzyme hasatherogenic action, by degrading apolipoproteins and preventing theabsorption of cholesterol by HDL. The action of chymase leads to releaseand activation of the cytokine interleukin 1 with its pro-inflammatoryproperties. Furthermore, it contributes to production of endothelin 1(Bacani and Frishman, Cardiol. Rev. 14 (4) (2006), 187-193). Anaccumulation of chymase-positive mast cells has been found in biopsiesof patients having atopic dermatitis, Crohn's disease, chronic hepatitisand hepatic cirrhosis, and also idiopathic interstitial pneumonia(Dogrell S. A., Expert Opin. Ther. Patents 18 (2008), 485-499).

The possibility of using chymase inhibitors for the treatment ofdifferent diseases has been demonstrated in numerous studies involvinganimal experimentation. Inhibition of chymase can be useful for thetreatment of myocardial infarction. Jin et al. (Pharmacol. Exp. Ther.309 (2004), 409-417) showed that a ligature of the coronary artery indogs led to ventricular arrhythmias and elevated production ofangiotensin II and chymase activity in the heart. Intravenousadministration of the chymase inhibitor TY-501076 reduced chymaseactivity and the angiotensin II concentration in the plasma, andsuppressed the occurrence of arrhythmias. A positive effect of chymaseinhibition was shown in an in vivo model for myocardial infarction inhamsters. Treatment of the animals with the chymase inhibitor BCEABreduced chymase activity, improved haemodynamics and reduced mortality(Jin et al., Life Sci. 71 (2002), 437-446). In the cardiomyopathicSyrian hamster, where the number of mast cells in the heart is elevated,oral treatment of the animals with the chymase inhibitor reduced cardiacfibrosis by 50% (Takai et al., Jpn. J. Pharmacol. 86 (2001), 124-126).In a tachycardia-induced heart failure model in dogs, chymase inhibitionwith SUN-C82257 led to reduction in the number of mast cells and infibrosis in the heart. In addition, the diastolic function of the heartwas improved after the treatment (Matsumoto et al., Circulation 107(2003), 2555-2558).

Inhibition of chymase thus constitutes an effective principle in thetreatment of cardiovascular disorders, inflammation and allergicdisorders, and various fibrotic disorders.

WO 2007/150011 and WO 2009/049112 disclose a process for preparingpyrimidinetriones with glycine substituents. WO 2008/056257 describestriazinediones as GABA-B receptor modulators for treatment of CNSdisorders. WO 2008/103277 discloses various nitrogen heterocycles fortreatment of cancer. WO 2009/156182 describes uracil derivatives forsuppression or reduction of resistance development in the course ofcytostatic treatment.

It was an object of the present invention to provide novel substanceswhich act as inhibitors of chymase and are suitable as such fortreatment and/or prophylaxis of disorders, especially cardiovasculardisorders.

The present invention relates to compounds of the general formula (I)

in whichR¹ is hydrogen or (C₁-C₄)-alkyl,R² is a group of the formula

-   -   where    -   * is the attachment site to the uracil nitrogen atom,    -   A is —CH₂— or oxygen,    -   m is a number 0, 1 or 2,    -   R⁴ is halogen, difluoromethyl, trifluoromethyl, (C₁-C₄)-alkyl,        difluoromethoxy, trifluoromethoxy or (C₁-C₄)-alkoxy,    -   R^(5A) is hydrogen or deuterium,    -   R^(5B) is hydrogen, deuterium or (C₁-C₄)-alkyl,    -   R⁶ is hydrogen or fluorine,    -   R⁷ is hydrogen or fluorine,    -   R⁸ is halogen, difluoromethyl, trifluoromethyl, (C₁-C₄)-alkyl or        nitro,    -   R⁹ is hydrogen, halogen, difluoromethyl, trifluoromethyl,        (C₁-C₄)-alkyl, nitro or (C₁-C₄)-alkylthio,        R³ is a group of the formula

-   -   where    -   # is the attachment site to the uracil nitrogen atom,    -   the ring Q is 5- to 7-membered heterocyclyl or 5- or 6-membered        heteroaryl,        -   in which 5- to 7-membered heterocyclyl and 5- or 6-membered            heteroaryl may be substituted by 1 to 4 substituents            independently selected from the group of halogen,            difluoromethyl, trifluoromethyl, trideuteromethyl,            (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, oxo, hydroxyl,            (C₁-C₄)-alkylcarbonyl, (C₁-C₄)-alkoxycarbonyl, aminocarbonyl            and (C₁-C₄)-alkylsulphonyl,            -   in which (C₁-C₆)-alkyl and (C₃-C₇)-cycloalkyl may in                turn be substituted by 1 to 3 substituents independently                selected from the group of halogen, cyano,                trifluoromethyl, (C₃-C₇)-cycloalkyl, hydroxyl,                (C₁-C₄)-alkoxy and 4- to 7-membered heterocyclyl,        -   and            -   in which two (C₁-C₆)-alkyl radicals bonded to a carbon                atom of 5- to 7-membered heterocyclyl and 5- or                6-membered heteroaryl, together with the carbon atom to                which they are bonded, may form a 3- to 6-membered                carbocycle,    -   R²⁴ is halogen, (C₁-C₄)-alkyl or (C₁-C₄)-alkoxy,    -   n is a number 0, 1, 2 or 3,        and the salts, solvates and solvates of the salts thereof.        The present invention relates to compounds of the general        formula (I)

in whichR¹ is hydrogen or (C₁-C₄)-alkyl,R² is a group of the formula

-   -   where    -   * is the attachment site to the uracil nitrogen atom,    -   A is CH₂—, —CH₂—CH₂—, —O—CH₂-## or oxygen,        -   in which        -   ## is the attachment site to the phenyl ring,    -   m is a number 0, 1 or 2,    -   R⁴ is halogen, difluoromethyl, trifluoromethyl, (C₁-C₄)-alkyl,        difluoromethoxy, trifluoromethoxy or (C₁-C₄)-alkoxy,    -   R^(5A) is hydrogen or deuterium,    -   R^(5B) is hydrogen, deuterium or (C₁-C₄)-alkyl,    -   R⁶ is hydrogen or fluorine,    -   R⁷ is hydrogen or fluorine,    -   R⁸ is halogen, difluoromethyl, trifluoromethyl, (C₁-C₄)-alkyl or        nitro,    -   R⁹ is hydrogen, halogen, difluoromethyl, trifluoromethyl,        (C₁-C₄)-alkyl, nitro or (C₁-C₄)-alkylthio,        R³ is a group of the formula

-   -   where    -   # is the attachment site to the uracil nitrogen atom,    -   the ring Q is 5- to 7-membered heterocyclyl or 5- or 6-membered        heteroaryl,        -   in which 5- to 7-membered heterocyclyl and 5- or 6-membered            heteroaryl may be substituted by 1 to 4 substituents            independently selected from the group of halogen,            difluoromethyl, trifluoromethyl, trideuteromethyl,            (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, oxo, hydroxyl,            (C₁-C₄)-alkylcarbonyl, (C₁-C₄)-alkoxycarbonyl, aminocarbonyl            and (C₁-C₄)-alkylsulphonyl,            -   in which (C₁-C₆)-alkyl and (C₃-C₇)-cycloalkyl may in                turn be substituted by 1 to 3 substituents independently                selected from the group of halogen, cyano,                trifluoromethyl, (C₃-C₇)-cycloalkyl, hydroxyl,                (C₁-C₄)-alkoxy and 4- to 7-membered heterocyclyl,        -   and            -   in which two (C₁-C₆)-alkyl radicals bonded to a carbon                atom of 5- to 7-membered heterocyclyl and 5- or                6-membered heteroaryl, together with the carbon atom to                which they are bonded, may form a 3- to 6-membered                carbocycle,    -   R²⁴ is halogen, (C₁-C₄)-alkyl or (C₁-C₄)-alkoxy,    -   n is a number 0, 1, 2 or 3,        and the salts, solvates and solvates of the salts thereof.

Inventive compounds are the compounds of the formula (I) and the salts,solvates and solvates of the salts thereof, the compounds encompassed byformula (I) of the formulae specified hereinafter and the salts,solvates and solvates of the salts thereof, and the compoundsencompassed by formula (I) and specified hereinafter as working examplesand the salts, solvates and solvates of the salts thereof, to the extentthat the compounds encompassed by formula (I) and specified hereinafterare not already salts, solvates and solvates of the salts.

In the context of the present invention, preferred salts arephysiologically acceptable salts of the inventive compounds. Alsoencompassed are salts which are not themselves suitable forpharmaceutical applications but can be used, for example, for theisolation, purification or storage of the inventive compounds.

Physiologically acceptable salts of the inventive compounds include acidaddition salts of mineral acids, carboxylic acids and sulphonic acids,for example salts of hydrochloric acid, hydrobromic acid, sulphuricacid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid,toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonicacid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid,tartaric acid, malic acid, citric acid, fumaric acid, maleic acid andbenzoic acid.

Physiologically acceptable salts of the inventive compounds also includesalts of conventional bases, by way of example and with preferencealkali metal salts (e.g. sodium and potassium salts), alkaline earthmetal salts (e.g. calcium and magnesium salts) and ammonium saltsderived from ammonia or organic amines having 1 to 16 carbon atoms, byway of example and with preference ethylamine, diethylamine,triethylamine, N,N-ethyldiisopropylamine, monoethanolamine,diethanolamine, triethanolamine, dimethylaminoethanol,diethylaminoethanol, procaine, dicyclohexylamine, dibenzylamine,N-methylpiperidine, N-methylmorpholine, arginine, lysine, choline and1,2-ethylenediamine.

In the context of the invention, solvates refer to those forms of theinventive compounds which, in solid or liquid state, form a complex bycoordination with solvent molecules. Hydrates are a specific form of thesolvates in which the coordination is with water. Preferred solvates inthe context of the present invention are hydrates.

Depending on their structure, the inventive compounds may exist indifferent stereoisomeric forms, i.e. in the form of configurationalisomers or if appropriate also as conformational isomers (enantiomersand/or diastereomers, including those in the case of atropisomers). Thepresent invention therefore encompasses the enantiomers or diastereomersand the respective mixtures thereof. The stereoisomerically homogeneousconstituents can be isolated from such mixtures of enantiomers and/ordiastereomers in a known manner; chromatography processes are preferablyused for this purpose, especially HPLC chromatography on an achiral orchiral phase. Where the inventive compounds can occur in tautomericforms, the present invention encompasses all the tautomeric forms.

The present invention also encompasses all suitable isotopic variants ofthe inventive compounds. An isotopic variant of an inventive compound isunderstood here to mean a compound in which at least one atom within theinventive compound has been exchanged for another atom of the sameatomic number, but with a different atomic mass than the atomic masswhich usually or predominantly occurs in nature. Examples of isotopeswhich can be incorporated into an inventive compound are those ofhydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine,chlorine, bromine and iodine, such as ²H (deuterium), ³H (tritium), ¹³C,¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³²P, ³³P, ³³S, ³⁴S, ³⁵S, ³⁶S, ¹⁸F, ³⁶Cl, ⁸²Br, ¹²³I,¹²⁴I, ¹²⁹I and ¹³¹I. Particular isotopic variants of an inventivecompound, especially those in which one or more radioactive isotopeshave been incorporated, may be beneficial, for example, for theexamination of the mechanism of action or of the active ingredientdistribution in the body; due to comparatively easy preparability anddetectability, especially compounds labelled with ³H or ¹⁴C isotopes aresuitable for this purpose. In addition, the incorporation of isotopes,for example of deuterium, can lead to particular therapeutic benefits asa consequence of greater metabolic stability of the compound, forexample an extension of the half-life in the body or a reduction in theactive dose required; such modifications of the inventive compounds maytherefore in some cases also constitute a preferred embodiment of thepresent invention. Isotopic variants of the inventive compounds can beprepared by processes known to those skilled in the art, for example bythe methods described below and the instructions reproduced in theworking examples, by using corresponding isotopic modifications of theparticular reagents and/or starting compounds therein.

Moreover, the present invention also encompasses prodrugs of theinventive compounds. The term “prodrugs” refers here to compounds whichmay themselves be biologically active or inactive, but are convertedwhile present in the body, for example by a metabolic or hydrolyticroute, to inventive compounds.

In the context of the present invention, unless specified otherwise, thesubstituents are each defined as follows:

Alkyl in the context of the invention is a linear or branched alkylradical having the number of carbon atoms specified in each case.Preferred examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, isopentyl,1-ethylpropyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, n-hexyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,4-dimethylpentyl,4,4-dimethylpentyl and 1,4,4-trimethylpentyl.

Cycloalkyl in the context of the invention is a monocyclic saturatedalkyl radical having 3 to 7 carbon atoms. Preferred examples include:cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Alkylcarbonyl in the context of the invention is a linear or branchedalkyl radical having 1 to 4 carbon atoms and a carbonyl group attachedin the 1 position. Preferred examples include: methylcarbonyl,ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl,isobutylcarbonyl and tert-butylcarbonyl.

Alkoxy in the context of the invention is a linear or branched alkoxyradical having 1 to 4 carbon atoms. Preferred examples include: methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.

Alkoxycarbonyl in the context of the invention is a linear or branchedalkoxy radical having 1 to 4 carbon atoms and a carbonyl group attachedto the oxygen. Preferred examples include: methoxycarbonyl,ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl andtert-butoxycarbonyl.

Alkvlthio in the context of the invention is a linear or branched alkylradical which has 1 to 4 carbon atoms and is bonded via a sulphur atom.Preferred examples include: methylthio, ethylthio, n-propylthio,isopropylthio, 1-methylpropylthio, n-butylthio, iso-butylthio andtert-butylthio.

Alkylsulphonyl in the context of the invention is a linear or branchedalkyl radical which has 1 to 4 carbon atoms and is bonded via asulphonyl group. Preferred examples include: methylsulphonyl,ethylsulphonyl, n-propylsulphonyl, isopropylsulphonyl, n-butylsulphonyland tert-butylsulphonyl.

4- to 7-membered heterocyclyl in the context of the invention is amonocyclic saturated heterocycle which has a total of 4 to 7 ring atoms,contains one or two ring heteroatoms from the group of N, O, S, SOand/or SO₂ and is attached via a ring carbon atom or, where appropriate,a ring nitrogen atom. Examples include: azetidinyl, oxetanyl,pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl,piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl. Preferenceis given to: azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl,piperidinyl, piperazinyl, tetrahydropyranyl and morpholinyl.

5- to 7 membered heterocyclyl in the context of the invention is apartly unsaturated heterocycle which has a total of 5 to 7 ring atoms,contains 1 to 3 ring heteroatoms from the group of N, O, S and/or SO₂and is fused to the phenyl ring in R³. Examples include:dihydropyrrolyl, dihydroimidazolyl, dihydrothiazole dioxide,dihydrooxazolyl, dihydropyridyl, tetrahydropyrazinyl anddihydrooxazinyl.

Heteroaryl in the context of the invention is a monocyclic aromaticheterocycle (heteroaromatic) which has a total of 5 or 6 ring atoms,contains up to three identical or different ring heteroatoms from thegroup of N, O and/or S and is fused to the phenyl ring in R³. Examplesinclude: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl,oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl,thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl andtriazinyl. Preference is given to pyrazolyl, imidazolyl, thiazolyl andtriazolyl.

Halogen in the context of the invention includes fluorine, chlorine,bromine and iodine. Preference is given to chlorine or fluorine.

An oxo group in the context of the invention is an oxygen atom bondedvia a double bond to a carbon or sulphur atom.

In the formulae of the group that R² and R³ may represent, the end pointof the line marked by a symbol * or # or ## does not represent a carbonatom or a CH₂ group but is part of the bond to the respective atom towhich R² and R³ are bonded.

If radicals in the compounds according to the invention are substituted,the radicals may be mono- or polysubstituted, unless specifiedotherwise. In the context of the present invention, all radicals whichoccur more than once are defined independently of one another.Substitution by one or two identical or different substituents ispreferred. Very particular preference is given to substitution by onesubstituent.

In the context of the present invention, the term “treatment” or“treating” includes inhibition, retardation, checking, alleviating,attenuating, restricting, reducing, suppressing, repelling or healing ofa disease, a condition, a disorder, an injury or a health problem, orthe development, the course or the progress of such states and/or thesymptoms of such states. The term “therapy” is understood here to besynonymous with the term “treatment”.

The terms “prevention”, “prophylaxis” or “preclusion” are usedsynonymously in the context of the present invention and refer to theavoidance or reduction of the risk of contracting, experiencing,suffering from or having a disease, a condition, a disorder, an injuryor a health problem, or a development or advancement of such statesand/or the symptoms of such states.

The treatment or prevention of a disease, a condition, a disorder, aninjury or a health problem may be partial or complete.

Preference is given in the context of the present invention to compoundsof the formula (I) in which

R¹ is hydrogen, methyl or ethyl,R² is a group of the formula

-   -   where    -   * is the attachment site to the uracil nitrogen atom,    -   A is —CH₂— or oxygen,    -   R^(4A) is hydrogen, fluorine, chlorine, trifluoromethyl or        methyl,    -   R^(4B) is hydrogen, fluorine, chlorine, trifluoromethyl or        methyl,    -   with the proviso that at least one of the R^(4A) and R^(4B)        radicals is not hydrogen,    -   R^(5A) is hydrogen,    -   R^(5B) is hydrogen,    -   R⁶ is hydrogen,    -   R⁷ is hydrogen,    -   R⁸ is fluorine, chlorine, difluoromethyl, trifluoromethyl or        methyl,    -   R⁹ is fluorine, chlorine, difluoromethyl, trifluoromethyl or        methyl,        R³ is a group of the formula

-   -   where    -   # is the attachment site to the uracil nitrogen atom,    -   E¹ is CR¹¹ or N,        -   in which        -   R¹¹ is hydrogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl or            aminocarbonyl,    -   E² is CR¹² or N,        -   in which        -   R¹² is hydrogen, (C₁-C₄)-alkyl or (C₃-C₇)-cycloalkyl,    -   E³ is NR¹⁴ or S,        -   in which        -   R¹⁴ is hydrogen, (C₁-C₄)-alkyl or (C₃-C₇)-cycloalkyl,    -   G¹ is C═O or SO₂,    -   G² is CR^(16A)R^(16B), NR¹⁷, O or S,        -   in which        -   R^(16A) is hydrogen, fluorine, (C₁-C₄)-alkyl or hydroxyl,        -   R^(16B) is hydrogen, fluorine, chlorine, (C₁-C₄)-alkyl or            trifluoromethyl,        -   or        -   R^(16A) and R^(16B) together with the carbon atom to which            they are bonded form a 3- to 6-membered carbocycle,        -   R¹⁷ is hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl or            (C₁-C₄)-alkoxycarbonyl, in which (C₁-C₆)-alkyl may be            substituted by 1 to 3 substituents independently selected            from the group of fluorine, trifluoromethyl, cyano,            (C₃-C₇)-cycloalkyl, hydroxyl, trifluoromethoxy,            (C₁-C₄)-alkoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and            pyrrolidinyl,    -   G³ is CR^(18A)R^(18B), NR¹⁹, O or S,        -   in which        -   R^(18A) is hydrogen, fluorine, (C₁-C₄)-alkyl or hydroxyl,        -   R^(18B) is hydrogen, fluorine, chlorine, (C₁-C₄)-alkyl or            trifluoromethyl,        -   or        -   R^(18A) and R^(18B) together with the carbon atom to which            they are bonded form a 3- to 6-membered carbocycle,        -   R¹⁹ is hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl or            (C₁-C₄)-alkoxycarbonyl, in which (C₁-C₆)-alkyl may be            substituted by 1 to 3 substituents independently selected            from the group of fluorine, trifluoromethyl, cyano,            (C₃-C₇)-cycloalkyl, hydroxyl, trifluoromethoxy,            (C₁-C₄)-alkoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and            pyrrolidinyl,    -   G⁴ is CH₂, C═O or SO₂,    -   K¹ is CH₂ or O,    -   K² is CH₂ or O,    -   with the proviso that only one of the K¹ and K² groups is O,    -   D¹, D², D³ and D⁴ are each independently CR²³ or N,        -   in which        -   R²³ is hydrogen, halogen, (C₁-C₆)-alkyl or            (C₃-C₇)-cycloalkyl, with the proviso that not more than 2 of            the D¹, D², D³ and D⁴ groups are N,    -   R²⁴ is fluorine or methyl,    -   n is a number 0 or 1,    -   R¹⁰ is (C₁-C₄)-alkyl or (C₃-C₇)-cycloalkyl,        -   in which (C₁-C₄)-alkyl may be substituted by 1 or 2            substituents independently selected from the group of            fluorine, trifluoromethyl, cyclopropyl, cyclobutyl,            hydroxyl, methoxy, ethoxy, azetidinyl, oxetanyl,            tetrahydrofuranyl and pyrrolidinyl,    -   R¹³ is hydrogen, (C₁-C₄)-alkyl or (C₃-C₇)-cycloalkyl,    -   R¹⁵ is hydrogen, (C₁-C₆)-alkyl or (C₃-C₇)-cycloalkyl,        -   in which (C₁-C₆)-alkyl may be substituted by 1 or 2            substituents independently selected from the group of            fluorine, trifluoromethyl, cyclopropyl, cyclobutyl,            hydroxyl, methoxy, ethoxy, azetidinyl, oxetanyl,            tetrahydrofuranyl and pyrrolidinyl,    -   R²⁰ is hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl or        (C₁-C₄)-alkylcarbonyl, in which (C₁-C₆)-alkyl may be substituted        by 1 or 2 substituents independently selected from the group of        fluorine, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxyl,        methoxy, ethoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and        pyrrolidinyl,    -   R²¹ is hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl or        (C₁-C₄)-alkylsulphonyl,    -   R^(22A) is hydrogen or (C₁-C₄)-alkyl,    -   R^(22B) is hydrogen or (C₁-C₄)-alkyl,    -   or    -   R^(22A) and R^(22B) together with the carbon atom to which they        are bonded form a carbonyl group, and the salts, solvates and        solvates of the salts thereof.

Preference is given in the context of the present invention to compoundsof the formula (I) in which

R¹ is hydrogen, methyl or ethyl,R² is a group of the formula

-   -   where    -   * is the attachment site to the uracil nitrogen atom,    -   A is CH₂—, —CH₂—CH₂—, —O—CH₂-## or oxygen,        -   in which        -   ## is the attachment site to the phenyl ring,    -   R^(4A) is hydrogen, fluorine, chlorine, trifluoromethyl or        methyl,    -   R^(4B) is hydrogen, fluorine, chlorine, trifluoromethyl or        methyl,    -   with the proviso that at least one of the R^(4A) and R^(4B)        radicals is not hydrogen,    -   R^(5A) is hydrogen,    -   R^(5B) is hydrogen,    -   R⁶ is hydrogen,    -   R is hydrogen,    -   R⁸ is fluorine, chlorine, difluoromethyl, trifluoromethyl or        methyl,    -   R⁹ is fluorine, chlorine, difluoromethyl, trifluoromethyl or        methyl,        R³ is a group of the formula

-   -   where    -   # is the attachment site to the uracil nitrogen atom,    -   E¹ is CR¹¹ or N,        -   in which        -   R¹¹ is hydrogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl or            aminocarbonyl,    -   E² is CR¹² or N,        -   in which        -   R¹² is hydrogen, (C₁-C₄)-alkyl or (C₃-C₇)-cycloalkyl,    -   E³ is NR¹⁴ or S,        -   in which        -   R¹⁴ is hydrogen, (C₁-C₄)-alkyl or (C₃-C₇)-cycloalkyl,    -   G¹ is C═O or SO₂,    -   G² is CR^(16A)R^(16B), NR¹⁷, O or S,        -   in which        -   R^(16A) is hydrogen, fluorine, (C₁-C₄)-alkyl or hydroxyl,        -   R^(16B) is hydrogen, fluorine, chlorine, (C₁-C₄)-alkyl or            trifluoromethyl,        -   or        -   R^(16A) and R^(16B) together with the carbon atom to which            they are bonded form a 3- to 6-membered carbocycle,        -   R¹⁷ is hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl or            (C₁-C₄)-alkoxycarbonyl, in which (C₁-C₆)-alkyl may be            substituted by 1 to 3 substituents independently selected            from the group of fluorine, trifluoromethyl, cyano,            (C₃-C₇)-cycloalkyl, hydroxyl, trifluoromethoxy,            (C₁-C₄)-alkoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and            pyrrolidinyl,    -   G³ is CR^(18A)R^(18B), NR¹⁹, O or S,        -   in which        -   R^(18A) is hydrogen, fluorine, (C₁-C₄)-alkyl or hydroxyl,        -   R^(18B) is hydrogen, fluorine, chlorine, (C₁-C₄)-alkyl or            trifluoromethyl,        -   or        -   R^(18A) and R^(18B) together with the carbon atom to which            they are bonded form a 3- to 6-membered carbocycle,        -   R¹⁹ is hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl or            (C₁-C₄)-alkoxycarbonyl, in which (C₁-C₆)-alkyl may be            substituted by 1 to 3 substituents independently selected            from the group of fluorine, trifluoromethyl, cyano,            (C₃-C₇)-cycloalkyl, hydroxyl, trifluoromethoxy,            (C₁-C₄)-alkoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and            pyrrolidinyl,    -   G⁴ is CH₂, C═O or SO₂,    -   K¹ is CH₂ or O,    -   K² is CH₂ or O,    -   with the proviso that only one of the K¹ and K² groups is O,    -   D¹, D², D³ and D⁴ are each independently CR²³ or N,        -   in which        -   R²³ is hydrogen, halogen, (C₁-C₆)-alkyl or            (C₃-C₇)-cycloalkyl, with the proviso that not more than 2 of            the D¹, D², D³ and D⁴ groups are N,    -   R²⁴ is fluorine or methyl,    -   n is a number 0 or 1,    -   R¹⁰ is (C₁-C₄)-alkyl or (C₃-C₇)-cycloalkyl,        -   in which (C₁-C₄)-alkyl may be substituted by 1 or 2            substituents independently selected from the group of            fluorine, trifluoromethyl, cyclopropyl, cyclobutyl,            hydroxyl, methoxy, ethoxy, azetidinyl, oxetanyl,            tetrahydrofuranyl and pyrrolidinyl,    -   R¹³ is hydrogen, (C₁-C₄)-alkyl or (C₃-C₇)-cycloalkyl,    -   R¹⁵ is hydrogen, (C₁-C₆)-alkyl or (C₃-C₇)-cycloalkyl,        -   in which (C₁-C₆)-alkyl may be substituted by 1 or 2            substituents independently selected from the group of            fluorine, trifluoromethyl, cyclopropyl, cyclobutyl,            hydroxyl, methoxy, ethoxy, azetidinyl, oxetanyl,            tetrahydrofuranyl and pyrrolidinyl,    -   R²⁰ is hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl or        (C₁-C₄)-alkylcarbonyl,        -   in which (C₁-C₆)-alkyl may be substituted by 1 or 2            substituents independently selected from the group of            fluorine, trifluoromethyl, cyclopropyl, cyclobutyl,            hydroxyl, methoxy, ethoxy, azetidinyl, oxetanyl,            tetrahydrofuranyl and pyrrolidinyl,    -   R²¹ is hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl or        (C₁-C₄)-alkylsulphonyl,    -   R^(22A) is hydrogen or (C₁-C₄)-alkyl,    -   R^(22B) is hydrogen or (C₁-C₄)-alkyl,    -   or    -   R^(22A) and R^(22B) together with the carbon atom to which they        are bonded form a carbonyl group, and the salts, solvates and        solvates of the salts thereof.        Particular preference is given in the context of the present        invention to compounds of the formula (I) in which        R¹ is hydrogen,        R² is a group of the formula

-   -   where    -   * is the attachment site to the uracil nitrogen atom,    -   A is —CH₂—,    -   R^(4A) is chlorine or trifluoromethyl,    -   R^(4B) is hydrogen,        R³ is a group of the formula

-   -   where    -   # is the attachment site to the uracil nitrogen atom,    -   E¹ is CR¹¹        -   in which        -   R¹¹ is hydrogen,    -   E² is N,    -   G¹ is C═O,    -   G² is CR^(16A)R^(16B), NR¹⁷, O or S,        -   in which        -   R^(16A) is hydrogen, fluorine, methyl or hydroxyl,        -   R^(16B) is hydrogen, fluorine, methyl or trifluoromethyl,        -   or        -   R^(16A) and R^(16B) together with the carbon atom to which            they are bonded form a cyclopropyl ring,        -   R¹⁷ is hydrogen, (C₁-C₄)-alkyl or (C₃-C₅)-cycloalkyl,            -   in which (C₁-C₄)-alkyl may be substituted by 1 to 3                substituents independently selected from the group of                fluorine, trifluoromethyl, cyano, cyclopropyl,                cyclobutyl, hydroxyl, trifluoromethoxy, methoxy, ethoxy,                azetidinyl, oxetanyl, tetrahydrofuranyl and                pyrrolidinyl,    -   R²⁴ is hydrogen or fluorine,    -   R¹⁰ is (C₁-C₄)-alkyl,    -   R¹⁵ is hydrogen, methyl or ethyl,        -   in which methyl and ethyl may be substituted by 1            substituent selected from the group of fluorine,            trifluoromethyl and cyclopropyl,            and the salts, solvates and solvates of the salts thereof.            Preference is also given in the context of the present            invention to compounds of the formula (I) in which            R¹ is hydrogen,            R² is a group of the formula

-   -   where    -   * is the attachment site to the uracil nitrogen atom,    -   R^(5A) is hydrogen,    -   R^(5B) is hydrogen,    -   R⁶ is hydrogen,    -   R⁷ is hydrogen,    -   R⁸ is fluorine, chlorine or trifluoromethyl,    -   R⁹ is fluorine, chlorine, trifluoromethyl or methyl,        R³ is a group of the formula

-   -   where    -   # is the attachment site to the uracil nitrogen atom,    -   E¹ is CR¹        -   in which        -   R¹¹ is hydrogen,    -   E² is N,    -   G¹ is C═O,    -   G² is CR^(16A)R^(16B), NR¹⁷, O or S,        -   in which        -   R^(16A) is hydrogen, fluorine, methyl or hydroxyl,        -   R^(16B) is hydrogen, fluorine, methyl or trifluoromethyl,        -   or        -   R^(16A) and R^(16B) together with the carbon atom to which            they are bonded form a cyclopropyl ring,        -   R¹⁷ is hydrogen, (C₁-C₄)-alkyl or (C₃-C₅)-cycloalkyl,            -   in which (C₁-C₄)-alkyl may be substituted by 1 to 3                substituents independently selected from the group of                fluorine, trifluoromethyl, cyano, cyclopropyl,                cyclobutyl, hydroxyl, trifluoromethoxy, methoxy, ethoxy,                azetidinyl, oxetanyl, tetrahydrofuranyl and                pyrrolidinyl,    -   R²⁴ is hydrogen or fluorine,    -   R¹⁰ is (C₁-C₄)-alkyl,    -   R¹⁵ is hydrogen, methyl or ethyl,        -   in which methyl and ethyl may be substituted by 1            substituent selected from the group of fluorine,            trifluoromethyl and cyclopropyl,            and the salts, solvates and solvates of the salts thereof.            Preference is also given in the context of the present            invention to compounds of the formula (I) in which            R¹ is hydrogen, methyl or ethyl,            R² is a group of the formula

-   -   where    -   * is the attachment site to the uracil nitrogen atom,    -   A is —CH₂—,    -   R^(4A) is chlorine or trifluoromethyl,    -   R^(4B) is hydrogen,        and the salts, solvates and solvates of the salts thereof.        Preference is also given in the context of the present invention        to compounds of the formula (I) in which        R³ is a group of the formula

-   -   where    -   # is the attachment site to the uracil nitrogen atom,    -   E¹ is CR¹¹ or N,        -   in which        -   R¹¹ is hydrogen, methyl, ethyl or aminocarbonyl,    -   E² is CR¹² or N,        -   in which        -   R¹² is hydrogen,    -   G¹ is C═O or SO₂,    -   G² is CR^(16A)R^(16B), NR¹⁷, O or S,        -   in which        -   R^(16A) is hydrogen, fluorine, methyl or hydroxyl,        -   R^(16B) is hydrogen, fluorine, chlorine, methyl or            trifluoromethyl,        -   or        -   R^(16A) and R^(16B) together with the carbon atom to which            they are bonded form a cyclopropyl ring,        -   R¹⁷ is hydrogen, (C₁-C₄)-alkyl, cyclopropyl or cyclobutyl,            -   in which (C₁-C₄)-alkyl may be substituted by 1 or 2                substituents independently selected from the group of                fluorine, trifluoromethyl, cyclopropyl, cyclobutyl,                hydroxyl, azetidinyl and oxetanyl,    -   G³ is CR^(18A)R^(18B)        -   in which        -   R^(18A) is hydrogen, fluorine, methyl or hydroxyl,        -   R^(18B) is hydrogen, fluorine, methyl or trifluoromethyl,    -   G⁴ is C═O,    -   K¹ is CH₂ or O,    -   K² is CH₂,    -   R²⁴ is hydrogen, fluorine or methyl,    -   R¹⁰ is methyl or ethyl,    -   R¹⁵ is methyl or ethyl,    -   R²⁰ is hydrogen, methyl, ethyl or methylcarbonyl,    -   R²¹ is methyl or ethyl,    -   R^(22A) and R^(22B) together with the carbon atom to which they        are bonded form a carbonyl group, and the salts, solvates and        solvates of the salts thereof.        Preference is also given in the context of the present invention        to compounds of the formula (I) in which        R² is a group of the formula

-   -   where    -   * is the attachment site to the uracil nitrogen atom,    -   A is —CH₂—,    -   R^(4A) is chlorine or trifluoromethyl,    -   R^(4B) is hydrogen,    -   and the carbon atom bonded to the uracil nitrogen atom has R        configuration, and the salts, solvates and solvates of the salts        thereof.        Preference is also given in the context of the present invention        to compounds of the formula (I) in which        R² is a group of the formula

-   -   where    -   * is the attachment site to the uracil nitrogen atom,    -   A is —CH₂—,    -   R^(4A) is hydrogen, fluorine, chlorine, trifluoromethyl or        methyl,    -   R^(4B) is hydrogen, fluorine, chlorine, trifluoromethyl or        methyl,    -   with the proviso that at least one of the R^(4A) and R^(4B)        radicals is not hydrogen,    -   and the carbon atom bonded to the uracil nitrogen atom has R        configuration, and the salts, solvates and solvates of the salts        thereof.

The individual radical definitions specified in the particularcombinations or preferred combinations of radicals are, independently ofthe particular combinations of the radicals specified, also replaced asdesired by radical definitions of other combinations.

Very particular preference is given to combinations of two or more ofthe preferred ranges mentioned above.

The invention further provides a process for preparing inventivecompounds of the formula (I), characterized in that

-   [A] a compound of the formula (II)

-   -   in which    -   R^(1A) is (C₁-C₄)-alkyl,    -   T¹ is (C₁-C₄)-alkyl    -   T² is (C₁-C₄)-alkyl    -   is reacted in an inert solvent, optionally in the presence of a        suitable base, with a compound of the formula (III)

H₂N—R³  (III)

-   -   in which R³ is as defined above    -   to give a compound of the formula (IV)

-   -   in which R^(1A) and R³ are each as defined above,    -   this is then reacted in an inert solvent, in the presence of a        suitable base, with a compound of the formula (V)

X¹—R²  (V)

-   -   in which R² is as defined above    -   and    -   X¹ is hydroxyl or a suitable leaving group, especially chlorine,        bromine or iodine    -   to give a compound of the formula (I-1)

-   -   in which R^(1A), R² and R³ are each as defined above,

-   or

-   [B] a compound of the formula (VI)

-   -   in which R^(1A) and T¹ are each as defined above and    -   T³ is (C₁-C₄)-alkyl    -   is converted in an inert solvent or else without solvent with a        compound of the formula (III) to a compound of the formula (VII)

-   -   in which R^(1A), R³ and T³ are each as defined above,    -   this is subsequently reacted in an inert solvent with        chlorosulphonyl isocyanate to give a compound of the        formula (IV) and this is subsequently converted analogously to        process [A] to a compound of the formula (I-1),

-   or

-   [C] a compound of the formula (VIII)

in which R² is as defined aboveis reacted in an inert solvent with a compound of the formula (IX)

in which R^(1A) and T¹ are each as defined above andT⁵ is (C₁-C₄)-alkyland cyclized in the presence of a suitable base to give a compound ofthe formula (X)

in which R^(1A) and R² are each as defined above,

-   and this is then reacted in an inert solvent, in the presence of a    suitable catalyst and a suitable base, with a compound of the    formula (XI)

in which R³ is as defined above, and

-   -   T⁶ is hydrogen, (C₁-C₄)-alkyl, or the two T⁶ radicals together        form a —C(CH₃)₂—C(CH₃)₂— bridge to give a compound of the        formula (I-1),

-   or

-   [D] a compound of the formula (I-1) is hydrolysed in an inert    solvent in the presence of a suitable acid or base to give a    compound of the formula (I-2)

-   -   in which R² and R³ are each as defined above, and    -   R^(1B) is hydrogen,        any protecting groups are detached and/or the compounds of the        formulae (I-1) and (I-2) are, where appropriate, converted with        the appropriate (i) solvents and/or (ii) bases or acids to the        solvates, salts and/or solvates of the salts thereof.

The compounds of the formulae (I-1) and (1-2) together form the group ofinventive compounds of the formula (I).

Inert solvents for the process steps (II)+(III)→(IV), (VI)+(III)→(VII)and (VIII)+(IX)→(X) are, for example, ethers such as diethyl ether,dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycoldimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane,cyclohexane or mineral oil fractions, halohydrocarbons such asdichloromethane, 1,2-dichloroethane, trichloroethylene or chlorobenzene,alcohols such as methanol, ethanol, n-propanol, isopropanol orn-butanol, or other solvents such as dimethylformamide, dimethylsulphoxide, N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidinone(NMP), pyridine, acetone, 2-butanone or acetonitrile. It is likewisepossible to use mixtures of the solvents mentioned. Preference is givento using ethanol.

Suitable bases for the process steps (II)+(III)→(IV) and (VIII)+(IX)→(X)are alkali metal alkoxides such as sodium or potassium methoxide, sodiumor potassium ethoxide or sodium or potassium tert-butoxide, alkali metalhydrides such as sodium or potassium hydride, amides such as sodiumamide, lithium or potassium bis(trimethylsilyl)amide or lithiumdiisopropylamide, or organic bases such as triethylamine,diisopropylethylamine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or1,4-diazabicyclo[2.2.2]octane (DABCO®) or phosphazene bases, for example1-[N-tert-butyl-P,P-di(pyrrolidin-1-yl)-phosphorimidoyl]pyrrolidine orN′″-tert-butyl-N,N,N′,N-tetramethyl-N″-[tris(dimethylamino)-lambda⁵-phosphanylidene]phosphoramideimide. Preference is given to sodium ethoxide and potassiumtert-butoxide.

The base is generally used here in an amount of 1 to 5 mol, preferablyin an amount of 1.2 to 3 mol, based on 1 mol of the compound of theformula (II) or (IX).

The conversions (II)+(III)→(IV), (VI)+(III)→(VII) and (VIII)+(IX)→(X)are effected generally within a temperature range from 0° C. to +150°C., preferably at +20° C. to +120° C., optionally in a microwave. Thereaction can be performed at standard, elevated or reduced pressure (forexample from 0.5 to 5 bar). In general, standard pressure is employed.

If X¹═OH, the conversion (IV)+(V)→(I-1) is effected under Mitsunobuconditions [see: a) Hughes, D. L. “The Mitsunobu Reaction” OrganicReactions; John Wiley & Sons, Ltd, 1992, vol. 42, p. 335. b) Hughes, D.L. Org. Prep. Proceed. Int. 1996, 28, 127]. The Mitsunobu reaction iseffected using triphenylphosphine, or tri-n-butylphosphine,1,2-bis(diphenylphosphino)ethane (DPPE), diphenyl(2-pyridyl)phosphine(Ph2P-Py), (p-dimethylaminophenyl)diphenylphosphine (DAP-DP),tris(4-dimethylaminophenyl)phosphine (tris-DAP), and a suitable dialkylazodicarboxylate, for example diethyl azodicarboxylate (DEAD),diisopropyl azodicarboxylate (DIAD), di-tert-butyl azodicarboxylate,N,N,N′N′-tetramethylazodicarboxamide (TMAD),1,1′-(azodicarbonyl)dipiperidine (ADDP) or4,7-dimethyl-3,5,7-hexahydro-1,2,4,7-tetrazocin-3,8-dione (DHTD).Preference is given to using triphenylphosphine and diisopropylazodicarboxylate (DIAD).

Inert solvents for the Mitsunobu reaction (IV)+(V)→(I-1) are, forexample, ethers such as tetrahydrofuran, diethyl ether, hydrocarbonssuch as benzene, toluene, xylene, halohydrocarbons such asdichloromethane, dichloroethane or other solvents such as acetonitrileor dimethylformamide (DMF). It is likewise possible to use mixtures ofthe solvents mentioned. Preference is given to using THF or a mixture ofTHF and DMF.

The Mitsunobu reaction (IV)+(V)→(I-1) is effected generally within atemperature range from −78° C. to +180° C., preferably at 0° C. to +50°C., optionally in a microwave. The conversions can be performed atstandard, elevated or reduced pressure (for example from 0.5 to 5 bar).

If X¹ is a suitable leaving group, the conversion (IV)+(V)→(I-1) iseffected under conditions for a nucleophilic substitution. In that case,inert solvents for the process step (IV)+(V)→(I-1) are, for example,ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethylether or diethylene glycol dimethyl ether, hydrocarbons such as benzene,toluene, xylene, hexane, cyclohexane or mineral oil fractions,halohydrocarbons such as dichloromethane, trichloromethane,1,2-dichloroethane, trichloroethylene or chlorobenzene, or othersolvents such as dimethylformamide, dimethyl sulphoxide,N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidinone (NMP),pyridine, acetone, 2-butanone or acetonitrile. It is likewise possibleto use mixtures of the solvents mentioned. Preference is given to usingacetonitrile, DMF or acetonitrile in a mixture with dimethylformamide.

Suitable bases for the process step (IV)+(V)→(I-1) are customaryinorganic bases. These include especially alkali metal or alkaline earthmetal carbonates such as lithium, sodium, potassium, calcium or caesiumcarbonate, optionally with addition of an alkali metal iodide, forexample potassium iodide, alkali metal alkoxides such as sodium orpotassium methoxide, sodium or potassium ethoxide or sodium or potassiumtert-butoxide, alkali metal hydrides such as sodium or potassiumhydride, amides such as sodium amide, lithium or potassiumbis(trimethylsilyl)amide or lithium diisopropylamide. Preference isgiven to using potassium carbonate with potassium iodide or sodiumhydride.

The base is generally used here in an amount of 1 to 5 mol, preferablyin an amount of 1.2 to 3 mol, based on 1 mol of the compound of theformula (IV).

The conversion (IV)+(V)→(I-1) is effected generally within a temperaturerange from 0° C. to +100° C., preferably at +20° C. to +80° C.,optionally in a microwave. The reaction can be performed at standard,elevated or reduced pressure (for example from 0.5 to 5 bar). Ingeneral, standard pressure is employed.

Inert solvents for the process step (VII)→(IV) are, for example, etherssuch as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl etheror diethylene glycol dimethyl ether, hydrocarbons such as benzene,toluene, xylene, hexane, cyclohexane or mineral oil fractions, or othersolvents such as chlorobenzene, dimethylformamide, dimethyl sulphoxide,N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidinone (NMP),pyridine, acetone, 2-butanone or acetonitrile. It is likewise possibleto use mixtures of the solvents mentioned. Preference is given to usingtoluene.

The conversion (VII)→(IV) is effected generally within a temperaturerange from 0° C. to +150° C., preferably at +20° C. to +120° C.,optionally in a microwave. The reaction can be performed at standard,elevated or reduced pressure (for example from 0.5 to 5 bar). Ingeneral, standard pressure is employed.

The process step (X)+(XI)→(I-1) is similar to a conversion called theChan-Lam coupling in the literature. Inert solvents for the process step(X)+(XI)→(I-1) are ethers such as 1,4-dioxane or tetrahydrofuran,halohydrocarbons such as dichloromethane, trichloromethane,1,2-dichloroethane, or other solvents such as dimethylformamide (DMF),N-methylpyrrolidone (NMP), acetonitrile or dimethyl sulphoxide (DMSO).It is likewise possible to use mixtures of the solvents mentioned.Preference is given to a mixture of acetonitrile and DMSO when (XI) is aboronic ester or a trifluoroborate salt, or dichloromethane when (XI) isa boronic acid. In some cases, the addition of molecular sieve isadvantageous.

Suitable bases for the process step (X)+(XI)→(I-1) are pyridine,pyridine derivatives, for example DMAP or organic tertiary amines, forexample diisopropylethylamine or triethylamine. Preference is given totriethylamine when (XI) is a boronic ester or a trifluoroborate salt, orpyridine when (XI) is a boronic acid.

Suitable catalysts for the process step (X)+(XI)→(I-1) are copper(II)salts, for example copper(II) acetate or copper(II) triflate, preferencebeing given to copper(II) acetate.

The process step (X)+(XI)→(I-1) is performed under air or under anoxygenous atmosphere.

The reaction (X)+(XI)→(I-1) is generally performed within a temperaturerange from 0° C. to +150° C., preferably at +20° C. to +80° C.

The hydrolysis of the ester group R^(1A) of the compound (I-1) tocompounds of the formula (I-2) is effected by treating the esters ininert solvents with acids or bases, in which latter case the saltsformed at first are converted to the free carboxylic acids by treatingwith acid. In general, the ester hydrolysis is preferably effected withacids. Suitable inert solvents for these reactions are water, diethylether, tetrahydrofuran, dioxane or glycol dimethyl ether, or othersolvents such as acetonitrile, acetic acid, dimethylformamide ordimethyl sulphoxide. It is likewise possible to use mixtures of thesolvents mentioned. In the case of a basic ester hydrolysis, preferenceis given to using mixtures of water with dioxane, tetrahydrofuran oracetonitrile. For the hydrolysis of tert-butyl esters, the solvent usedin the case of reaction with trifluoroacetic acid is preferablydichloromethane, and in the case of reaction with hydrogen chloridepreferably tetrahydrofuran, diethyl ether or dioxane. For the hydrolysisof other esters under acidic conditions, preference is given to aceticacid or a mixture of acetic acid and water.

Suitable bases are the alkali metal or alkaline earth metalhydrogencarbonates such as sodium or potassium hydrogencarbonate.Preference is given to sodium hydrogencarbonate.

Suitable acids for the ester hydrolysis are generally sulphuric acid,hydrogen chloride/hydrochloric acid, hydrogen bromide/hydrobromic acid,phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulphonicacid, methanesulphonic acid or trifluoromethanesulphonic acid ormixtures thereof, optionally with addition of water. Preference is givento hydrogen chloride or trifluoroacetic acid in the case of thetert-butyl esters, and to hydrochloric acid in a mixture with aceticacid, and to sulphuric acid in a mixture with acetic acid and water inthe case of the methyl esters and ethyl esters.

The ester hydrolysis is effected generally within a temperature rangefrom 0° C. to 180° C., preferably at +20° C. to 120° C.

These conversions can be performed at standard, elevated or reducedpressure (for example from 0.5 to 5 bar). In general, standard pressureis employed in each case.

The preparation of the inventive compounds can be illustrated by way ofexample by the following synthesis schemes (Schemes 1 to 3):

The compounds of the formulae (II), (III), (V), (VI), (VIII), (IX) and(XI) are commercially available or known from the literature, or can beprepared in analogy to processes known from the literature.

Further inventive compounds can optionally also be prepared byconversions of functional groups of individual substituents, especiallythose listed for R³, proceeding from compounds of the formula (I)obtained by above processes. These conversions are performed asdescribed in the present experimental section, by customary methodsknown to those skilled in the art and include, for example, reactionssuch as nucleophilic and electrophilic substitutions, oxidations,reductions, hydrogenations, transition metal-catalysed couplingreactions, eliminations, alkylation, amination, esterification, esterhydrolysis, etherification, ether cleavage, formation of carbonamides,and introduction and removal of temporary protecting groups, Theconversion of functional groups can be illustrated by way of example bythe following synthesis scheme (Scheme 4):

The inventive compounds have valuable pharmacological properties and canbe used for treatment and/or prophylaxis of diseases in humans andanimals.

The inventive compounds are chymase inhibitors and are thereforesuitable for treatment and/or prophylaxis of cardiovascular,inflammatory, allergic and/or fibrotic disorders.

In the context of the present invention, disorders of the cardiovascularsystem or cardiovascular disorders are understood to mean, for example,the following disorders: acute and chronic heart failure, arterialhypertension, coronary heart disease, stable and unstable anginapectoris, myocardial ischaemia, myocardial infarction, shock,atherosclerosis, cardiac hypertrophy, cardiac fibrosis, atrial andventricular arrhythmias, transitory and ischaemic attacks, stroke,pre-eclampsia, inflammatory cardiovascular disorders, peripheral andcardiac vascular disorders, peripheral perfusion disorders, arterialpulmonary hypertension, spasms of the coronary arteries and peripheralarteries, thromboses, thromboembolic disorders, oedema development, forexample pulmonary oedema, cerebral oedema, renal oedema or heartfailure-related oedema, and restenoses such as after thrombolysistreatments, percutaneous transluminal angioplasty (PTA), transluminalcoronary angioplasty (PTCA), heart transplants and bypass operations,and micro- and macrovascular damage (vasculitis), reperfusion damage,arterial and venous thromboses, microalbuminuria, myocardialinsufficiency, endothelial dysfunction, elevated levels of fibrinogenand of low-density LDL elevated concentrations of plasminogenactivator/inhibitor 1 (PAI-1).

In the context of the present invention, the term “heart failure” alsoincludes more specific or related types of disease, such as acutelydecompensated heart failure, right heart failure, left heart failure,global failure, ischaemic cardiomyopathy, dilated cardiomyopathy,congenital heart defects, heart valve defects, heart failure associatedwith heart valve defects, mitral stenosis, mitral insufficiency, aorticstenosis, aortic insufficiency, tricuspid stenosis, tricuspidinsufficiency, pulmonary valve stenosis, pulmonary valve insufficiency,combined heart valve defects, myocardial inflammation (myocarditis),chronic myocarditis, acute myocarditis, viral myocarditis, diabeticheart failure, alcoholic cardiomyopathy, cardiac storage disorders, anddiastolic and systolic heart failure.

The inventive compounds are further suitable for the prophylaxis and/ortreatment of polycystic kidney disease (PCKD) and of syndrome ofinappropriate ADH secretion (SIADH).

Furthermore, the inventive compounds are suitable for treatment and/orprophylaxis of renal disorders, especially of acute and chronic renalinsufficiency, and of acute and chronic kidney failure.

In the context of the present invention, the term acute renalinsufficiency encompasses acute manifestations of kidney disease, ofkidney failure and/or renal insufficiency with and without the need fordialysis, and also underlying or related renal disorders such as renalhypoperfusion, intradialytic hypotension, volume deficiency (e.g.dehydration, blood loss), shock, acute glomerulonephritis,haemolytic-uraemic syndrome (HUS), vascular catastrophe (arterial orvenous thrombosis or embolism), cholesterol embolism, acute Bence-Joneskidney in the event ofplasmacytoma, acute supravesicular or subvesicularefflux obstructions, immunological renal disorders such as kidneytransplant rejection, immune complex-induced renal disorders, tubulardilatation, hyperphosphataemia and/or acute renal disorderscharacterized by the need for dialysis, including in the case of partialresections of the kidney, dehydration through forced diuresis,uncontrolled blood pressure rise with malignant hypertension, urinarytract obstruction and infection and amyloidosis, and systemic disorderswith glomerular factors, such as rheumatological-immunological systemicdisorders, for example lupus erythematodes, renal artery thrombosis,renal vein thrombosis, analgesic nephropathy and renal tubular acidosis,and x-ray contrast agentand medicament-induced acute interstitial renaldisorders.

In the context of the present invention, the term chronic renalinsufficiency encompasses chronic manifestations of kidney disease, ofkidney failure and/or renal insufficiency with and without the need fordialysis, and also underlying or related renal disorders such as renalhypoperfusion, intradialytic hypotension, obstructive uropathy,glomerulopathy, glomerular and tubular proteinuria, renal oedema,haematuria, primary, secondary and chronic glomerulonephritis,membranous and membranoproliferative glomerulonephritis, Alportsyndrome, glomerulosclerosis, tubulointerstitial disorders, nephropathicdisorders such as primary and congenital kidney disease, renalinflammation, immunological renal disorders such as kidney transplantrejection, immune complex-induced renal disorders, diabetic andnon-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis,hypertensive nephrosclerosis and nephrotic syndrome, which can becharacterized diagnostically, for example, by abnormally reducedcreatinine and/or water excretion, abnormally elevated bloodconcentrations of urea, nitrogen, potassium and/or creatinine, alteredactivity of renal enzymes, for example glutamyl synthetase, alteredurine osmolarity or urine volume, elevated microalbuminuria,macroalbuminuria, glomerular and arteriolar lesions, tubular dilatation,hyperphosphataemia and/or the need for dialysis, and in the event ofrenal cell carcinoma, after partial resections of the kidney,dehydration through forced diuresis, uncontrolled blood pressure risewith malignant hypertension, urinary tract obstruction and infection andamyloidosis, and systemic disorders with glomerular factors, such asrheumatological-immunological systemic disorders, for example lupuserythematodes, and also renal artery stenosis, renal artery thrombosis,renal vein thrombosis, analgesic nephropathy and renal tubular acidosis.In addition, x-ray contrast agent- and medicament-induced chronicinterstitial renal disorders, metabolic syndrome and dyslipidaemia. Thepresent invention also encompasses the use of the inventive compoundsfor treatment and/or prophylaxis of sequelae of renal insufficiency, forexample pulmonary oedema, heart failure, uraemia, anaemia, electrolytedisturbances (for example hypercalaemia, hyponatraemia) and disturbancesin bone and carbohydrate metabolism.

In addition, the inventive compounds are also suitable for treatmentand/or prophylaxis of pulmonary arterial hypertension (PAH) and otherforms of pulmonary hypertension (PH), of chronic obstructive pulmonarydisease (COPD), of acute respiratory distress syndrome (ARDS), of acutelung injury (ALI), of alpha-1-antitrypsin deficiency (AATD), ofpulmonary fibrosis, of pulmonary emphysema (for example pulmonaryemphysema caused by cigarette smoke), of cystic fibrosis (CF), of acutecoronary syndrome (ACS), heart muscle inflammation (myocarditis) andother autoimmune cardiac disorders (pericarditis, endocarditis,valvolitis, aortitis, cardiomyopathy), cardiogenic shock, aneurysms,sepsis (SIRS), multiple organ failure (MODS, MOF), inflammationdisorders of the kidney, chronic intestinal disorders (IBD, Crohn'sDisease, UC), pancreatitis, peritonitis, rheumatoid disorders,inflammatory skin disorders and inflammatory eye disorders.

The inventive compounds can additionally be used for treatment and/orprophylaxis of asthmatic disorders of varying severity with intermittentor persistent characteristics (refractive asthma, bronchial asthma,allergic asthma, intrinsic asthma, extrinsic asthma, medicament- ordust-induced asthma), of various forms of bronchitis (chronicbronchitis, infectious bronchitis, eosinophilic bronchitis), ofBronchiolitis obliterans, bronchiectasis, pneumonia, idiopathicinterstitial pneumonia, farmer's lung and related disorders, coughs andcolds (chronic inflammatory cough, iatrogenic cough), inflammation ofthe nasal mucosa (including medicament-related rhinitis, vasomotoricrhinitis and seasonal allergic rhinitis, for example hay fever) and ofpolyps.

In addition, the inventive compounds are suitable for treatment and/orprophylaxis of fibrotic disorders of the internal organs, for example ofthe lung, the heart, the kidney, the bone marrow and in particular theliver, and also of dermatological fibroses and fibrotic eye disorders.In the context of the present invention, the term “fibrotic disorders”encompasses particularly the following terms: hepatic fibrosis,cirrhosis of the liver, pulmonary fibrosis, endomyocardial fibrosis,cardiomyopathy, nephropathy, glomerulonephritis, interstitial renalfibrosis, fibrotic damage resulting from diabetes, bone marrow fibrosisand similar fibrotic disorders, scleroderma, morphea, keloids,hypertrophic scarring (also following surgical procedures), naevi,diabetic retinopathy and proliferative vitroretinopathy.

In addition, the inventive compounds are suitable for control ofpostoperative scarring, for example resulting from glaucoma operations.

In addition, the inventive compounds can likewise be used cosmeticallyin the event of ageing and homifying skin.

In addition, the inventive compounds can also be used for treatmentand/or prophylaxis of dyslipidaemias (hypercholesterolaemia,hypertriglyceridaemia, elevated concentrations of the postprandialplasma triglycerides, hypoalphalipoproteinaemia, combinedhyperlipidaemias), nephropathy and neuropathy), cancers (skin cancer,brain tumours, breast cancer, bone marrow tumours, leukaemias,liposarcomas, carcinoma of the gastrointestinal tract, of the liver,pancreas, lung, kidney, urinary tract, prostate and genital tract, andalso malignant tumours in the lymphoproliferative system, for exampleHodgkin's and non-Hodgkin's lymphoma), of disorders of thegastrointestinal tract and of the abdomen (glossitis, gingivitis,periodontitis, oesophagitis, eosinophilic gastroenteritis, mastocytosis,Crohn's disease, colitis, proctitis, pruritus ani, diarrhoea, coeliacdisease, hepatitis, chronic hepatitis, hepatic fibrosis, cirrhosis ofthe liver, pancreatitis and cholecystitis), skin disorders (allergicskin disorders, psoriasis, acne, eczema, neurodermitis, various forms ofdermatitis, and also keratitis, bullosis, vasculitis, cellulitis,panniculitis, lupus erythematodes, erythema, lymphoma, skin cancer,Sweet's syndrome, Weber-Christian syndrome, scarring, warts,chillblains), of disorders of the skeletal bone and of the joints, andalso of the skeletal muscle (various forms of arthritis, various formsof arthropathies, scleroderma and of further disorders with aninflammatory or immunological component, for example paraneoplasticsyndrome, in the event of rejection reactions after organ transplantsand for wound healing and angiogenesis, especially in the case ofchronic wounds.

The inventive compounds of the formula (I) are additionally suitable fortreatment and/or prophylaxis of ophthalmologic disorders, for exampleglaucoma, normotensive glaucoma, high intraocular pressure andcombinations thereof, of age-related macular degeneration (AMD), of dryor non-exudative AMD, moist or exudative or neovascular AMD, choroidalneovascularization (CNV), detached retina, diabetic retinopathy,atrophic lesions to the retinal pigment epithelium (RPE), hypertrophiclesions to the retinal pigment epithelium (RPE), diabetic macularoedema, retinal vein occlusion, choroidal retinal vein occlusion,macular oedema, macular oedema due to retinal vein occlusion,angiogenesis at the front of the eye, for example corneal angiogenesis,for example following keratitis, cornea transplant or keratoplasty,corneal angiogenesis due to hypoxia (extensive wearing of contactlenses), pterygium conjunctiva, subretinal oedema and intraretinaloedema.

In addition, the inventive compounds of the formula (I) for treatmentand/or prophylaxis of elevated and high intraocular pressure resultingfrom traumatic hyphaema, periorbital oedema, postoperative viscoelasticretention, intraocular inflammation, use of corticosteroids, pupillaryblock or idiopathic causes, and of elevated intraocular pressurefollowing trabeculectomy and due to pre-operative conditions.

The present invention further provides for the use of the inventivecompounds for treatment and/or prophylaxis of disorders, especially ofthe aforementioned disorders.

The present invention further provides for the use of the inventivecompounds for production of a medicament for treatment and/orprophylaxis of disorders, especially of the aforementioned disorders.

The present invention further provides the inventive compounds for usein a method for treatment and/or prophylaxis of heart failure, pulmonaryhypertension, chronic obstructive pulmonary disease, asthma, kidneyfailure, nephropathy, fibrotic disorders of the internal organs anddermatological fibroses.

The inventive compounds can be employed alone or, if required, incombination with other active ingredients. The present inventiontherefore further provides medicaments comprising at least one of theinventive compounds and one or more further active ingredients,especially for treatment and/or prophylaxis of the aforementioneddisorders. Preferred examples of suitable active ingredient combinationsinclude: compounds which inhibit the signal transduction cascade, by wayof example and with preference from the group of the kinase inhibitors,especially from the group of the tyrosine kinase and/or serine/threoninekinase inhibitors;

compounds which inhibit the degradation and alteration of theextracellular matrix, by way of example and with preference inhibitorsof the matrix metalloproteases (MMPs), especially inhibitors ofstromelysin, collagenases, gelatinases and aggrecanases (in this contextparticularly of MMP-1, MMP-3, MMP-8, MMP-9, MMP-10, MMP-11 and MMP-13)and of metalloelastase (MMP-12);

compounds which block the binding of serotonin to its receptors, by wayof example and with preference antagonists of the 5-HT_(2b) receptor;

organic nitrates and NO donors, for example sodium nitroprusside,nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomineor SIN-1, and inhaled NO;

NO-independent but haem-dependent stimulators of soluble guanylatecyclase, such as especially the compounds described in WO 00/06568, WO00/06569, WO 02/42301 and WO 03/095451;

NO- and haem-independent activators of soluble guanylate cyclase, suchas especially the compounds described in WO 01/19355, WO 01/19776, WO01/19778, WO 01/19780, WO 02/070462 and WO 02/070510; prostacyclinanalogues, by way of example and with preference iloprost, beraprost,treprostinil or epoprostenol; compounds which inhibit soluble epoxidehydrolase (sEH), for example N,N′-dicyclohexylurea,12-(3-adamantan-1-yl-ureido)dodecanoic acid or1-adamantan-1-yl-3-{5-[2-(2-ethoxyethoxyl)ethoxy]pentyl}urea; compoundswhich influence the energy metabolism of the heart, by way of exampleand with preference etomoxir, dichloroacetate, ranolazine ortrimetazidine; compounds which inhibit the degradation of cyclicguanosine monophosphate (cGMP) and/or cyclic adenosine monophosphate(cAMP), for example inhibitors of phosphodiesterases (PDE) 1, 2, 3, 4and/or 5, especially PDE 5 inhibitors such as sildenafil, vardenafil andtadalafil;

antithrombotic agents, by way of example and with preference from thegroup of the platelet aggregation inhibitors, the anticoagulants or theprofibrinolytic substances;

hypotensive active ingredients, for example and with preference from thegroup of calcium antagonists, angiotensin AII antagonists, ACEinhibitors, vasopeptidase inhibitors, endothelin antagonists, renininhibitors, alpha-receptor blockers, beta-receptor blockers,mineralocorticoid receptor antagonists, and rho kinase inhibitors andthe diuretics;

vasopressin receptor antagonists, for example and with preferenceconivaptan, tolvaptan, lixivaptan, mozavaptan, satavaptan, SR-121463,RWJ 676070 or BAY 86-8050;

bronchodilatory agents, by way of example and with preference from thegroup of the beta-adrenergic receptor agonists, such as especiallyalbuterol, isoproterenol, metaproterenol, terbutalin, formoterol orsalmeterol, or from the group of the anticholinergics, such asespecially ipratropium bromide;

anti-inflammatory agents, by way of example and with preference from thegroup of the glucocorticoids, such as especially prednisone,prednisolone, methylprednisolone, triamcinolone, dexamethasone,beclomethasone, betamethasone, flunisolide, budesonide or fluticasone;and/or

active ingredients which modify lipid metabolism, by way of example andwith preference from the group of thyroid receptor agonists, cholesterolsynthesis inhibitors such as, by way of example and with preference,HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACATinhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gammaand/or PPAR-delta agonists, cholesterol absorption inhibitors, lipaseinhibitors, polymeric bile acid adsorbents, bile acid reabsorptioninhibitors and lipoprotein (a) antagonists.

In a preferred embodiment of the invention, the inventive compounds areused in combination with a kinase inhibitor, by way of example and withpreference bortezomib, canertinib, erlotinib, gefitinib, imatinib,lapatinib, lestaurtinib, lonafamib, pegaptinib, pelitinib, semaxanib,sorafenib, regorafenib, sunitinib, tandutinib, tipifamib, vatalanib,fasudil, lonidamine, leflunomide, BMS-3354825 or Y-27632.

In a preferred embodiment of the invention, the inventive compounds areused in combination with a serotonin receptor antagonist, by way ofexample and with preference PRX-08066.

Antithrombotic agents are preferably understood to mean compounds fromthe group of the platelet aggregation inhibitors, the anticoagulants orthe profibrinolytic substances.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with a platelet aggregation inhibitor, byway of example and with preference aspirin, clopidogrel, ticlopidin ordipyridamol.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with a thrombin inhibitor, by way of exampleand with preference ximelagatran, melagatran, bivalirudin or clexane.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with a GPIIb/IIIa antagonist, by way ofexample and with preference tirofiban or abciximab.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with a factor Xa inhibitor, by way ofexample and with preference rivaroxaban, DU-176b, fidexaban, razaxaban,fondaparinux, idraparinux, PMD-3112, YM-150, KFA-1982, EMD-503982,MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with heparin or a low molecular weight (LMW)heparin derivative.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with a vitamin K antagonist, by way ofexample and with preference coumarin.

Hypotensive agents are preferably understood to mean compounds from thegroup of calcium antagonists, angiotensin AII antagonists, ACEinhibitors, endothelin antagonists, renin inhibitors, alpha-receptorblockers, beta-receptor blockers, mineralocorticoid receptorantagonists, rho kinase inhibitors, and the diuretics.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with a calcium antagonist, by way of exampleand with preference nifedipine, amlodipine, verapamil or diltiazem.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with an alpha-1 receptor blocker, by way ofexample and with preference prazosin.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with a beta receptor blocker, by way ofexample and with preference propranolol, atenolol, timolol, pindolol,alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol,mepindolol, carazalol, sotalol, metoprolol, betaxolol, celiprolol,bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol,landiolol, nebivolol, epanolol or bucindolol.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with an angiotensin AII antagonist, by wayof example and with preference losartan, candesartan, valsartan,telmisartan or embursatan.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with an ACE inhibitor, by way of example andwith preference enalapril, captopril, lisinopril, ramipril, delapril,fosinopril, quinopril, perindopril or trandopril.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with an endothelin antagonist, by way ofexample and with preference bosentan, darusentan, ambrisentan orsitaxsentan.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with a renin inhibitor, by way of exampleand with preference aliskiren, SPP-600 or SPP-800.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with a mineralocorticoid receptorantagonist, by way of example and with preference spironolactone oreplerenone.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with a rho kinase inhibitor, by way ofexample and with preference fasudil, Y-27632, SLx-2119, BF-66851,BF-66852, BF-66853, KI-23095, SB-772077, GSK-269962A or BA-1049.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a diuretic, by way ofexample and with preference furosemide.

Agents which modify lipid metabolism are preferably understood to meancompounds from the group of CETP inhibitors, thyroid receptor agonists,cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors orsqualene synthesis inhibitors, of ACAT inhibitors, MTP inhibitors,PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterolabsorption inhibitors, polymeric bile acid adsorbents, bile acidreabsorption inhibitors, lipase inhibitors and lipoprotein(a)antagonists.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with a CETP inhibitor, by way of example andwith preference torcetrapib (CP-529 414), JJT-705 or CETP vaccine(Avant).

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with a thyroid receptor agonist, by way ofexample and with preference D-thyroxin, 3,5,3′-triiodothyronin (T3), CGS23425 or axitirome (CGS 26214).

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with a HMG-CoA reductase inhibitor from theclass of the statins, by way of example and with preference lovastatin,simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin orpitavastatin.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with a squalene synthesis inhibitor, by wayof example and with preference BMS-188494 or TAK-475.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with an ACAT inhibitor, by way of exampleand with preference avasimibe, melinamide, pactimibe, eflucimibe orSMP-797.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with an MTP inhibitor, by way of example andwith preference implitapide, BMS-201038, R-103757 or JTT-130.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with a PPAR-gamma agonist, by way of exampleand with preference pioglitazone or rosiglitazone.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with a PPAR-delta agonist, by way of exampleand with preference GW 501516 or BAY 685042.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with a cholesterol absorption inhibitor, byway of example and with preference ezetimibe, tiqueside or pamaqueside.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with a lipase inhibitor, by way of exampleand with preference orlistat.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with a polymeric bile acid adsorbent, by wayof example and with preference cholestyramine, colestipol, colesolvam,Cholestagel or colestimide.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with a bile acid reabsorption inhibitor, byway of example and with preference ASBT (=IBAT) inhibitors, for exampleAZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with a lipoprotein(a) antagonist, by way ofexample and with preference gemcabene calcium (CI-1027) or nicotinicacid.

The present invention further provides medicaments which comprise atleast one inventive compound, typically together with one or more inert,nontoxic, pharmaceutically suitable excipients, and the use thereof forthe aforementioned purposes.

The inventive compounds may act systemically and/or locally. For thispurpose, they can be administered in a suitable manner, for example bythe oral, parenteral, pulmonal, nasal, sublingual, lingual, buccal,rectal, dermal, transdermal, conjunctival, otic route, or as an implantor stent.

The inventive compounds can be administered in administration formssuitable for these administration routes.

Suitable administration forms for oral administration are those whichwork according to the prior art and release the inventive compoundsrapidly and/or in a modified manner and which contain the inventivecompounds in crystalline and/or amorphized and/or dissolved form, forexample tablets (uncoated or coated tablets, for example with gastricjuice-resistant or retarded-dissolution or insoluble coatings whichcontrol the release of the inventive compound), tablets or films/oblateswhich disintegrate rapidly in the oral cavity, films/lyophilizates orcapsules (for example hard or soft gelatin capsules), sugar-coatedtablets, granules, pellets, powders, emulsions, suspensions, aerosols orsolutions.

Parenteral administration can bypass an absorption step (e.g.intravenously, intraarterially, intracardially, intraspinally orintralumbally) or include an absorption (e.g. inhalatively,intramuscularly, subcutaneously, intracutaneously, percutaneously orintraperitoneally). Suitable administration forms for parenteraladministration include injection and infusion formulations in the formof solutions, suspensions, emulsions, lyophilizates or sterile powders.

For the other administration routes, suitable examples are inhalationmedicaments (including powder inhalers, nebulizers, aerosols), nasaldrops, solutions or sprays; tablets for lingual, sublingual or buccaladministration, films/oblates or capsules, suppositories, ear or eyepreparations, vaginal capsules, aqueous suspensions (lotions, shakingmixtures), lipophilic suspensions, ointments, creams, transdermaltherapeutic systems (e.g. patches), milk, pastes, foams, dustingpowders, implants or stents.

Oral and parenteral administration are preferred, especially oral,intravenous and inhalative administration.

The inventive compounds can be converted to the administration formslisted. This can be done in a manner known per se, by mixing with inert,nontoxic, pharmaceutically suitable excipients. These excipients includecarriers (for example microcrystalline cellulose, lactose, mannitol),solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersingor wetting agents (for example sodium dodecylsulphate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic andnatural polymers (for example albumin), stabilizers (e.g. antioxidants,for example ascorbic acid), dyes (e.g. inorganic pigments, for exampleiron oxides) and flavour and/or odour correctants.

In general, it has been found to be advantageous in the case ofparenteral administration to administer amounts of about 0.001 to 1mg/kg, preferably about 0.01 to 0.5 mg/kg, of body weight to achieveeffective results. In the case of oral administration, the dosage isabout 0.01 to 100 mg/kg, preferably about 0.01 to 20 mg/kg and mostpreferably 0.1 to 10 mg/kg of body weight.

In spite of this, it may be necessary to deviate from the amountsspecified, specifically depending on body weight, administration route,individual behaviour towards the active ingredient, type of formulation,and time or interval of administration. For instance, less than theaforementioned minimum amount may be sufficient in some cases, while theupper limit mentioned has to be exceeded in other cases. In the case ofadministration of greater amounts, it may be advisable to divide theminto several individual doses over the day.

The working examples which follow illustrate the invention. Theinvention is not limited to the examples.

The percentages in the tests and examples which follow are, unlessindicated otherwise, percentages by weight; parts are parts by weight.Solvent ratios, dilution ratios and concentration data for liquid/liquidsolutions, unless indicated otherwise, are based in each case on volume.

A. EXAMPLES Abbreviations

-   Ac acetyl-   aq. aqueous, aqueous solution-   br.d broad doublet (NMR)-   br.m broad multiplet (NMR)-   br.s broad singlet (NMR)-   br.t broad triplet (NMR)-   c concentration-   cat. catalytic-   TLC thin layer chromatography-   DCI direct chemical ionization (in MS)-   dist. distilled-   DIAD diisopropyl azodicarboxylate-   DIEA N,N-diisopropylethylamine-   DMAP 4-N,N-dimethylaminopyridine-   DMF dimethylformamide-   DMSO dimethyl sulphoxide-   DSC differential scanning thermography-   EDC N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride-   ee enantiomeric excess-   ent enantiomerically pure, enantiomer-   eq. equivalent(s)-   ESI electrospray ionization (in MS)-   Et ethyl-   GC-MS gas chromatography-coupled mass spectrometry-   h hour(s)-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HOBt 1-hydroxy-1H-benzotriazole hydrate-   HPLC high-pressure high-performance liquid chromatography-   conc. concentrated-   LC-MS liquid chromatography-coupled mass spectrometry-   Me methyl-   min minute(s)-   MPLC medium-pressure liquid chromatography-   MS mass spectrometry-   MTBE methyl tert-butyl ether-   NMR nuclear magnetic resonance spectrometry-   Pd/C palladium on activated carbon-   Ph phenyl-   PyBOP benzotriazol-1-yloxytris(pyrrolidino)phosphonium    hexafluorophosphate-   quant. quantitative (in the case of yield)-   rac racemic, racemate-   RT room temperature-   R_(t) retention time (in HPLC)-   m.p. melting point-   tBu tert-butyl-   tert tertiary-   TFA trifluoroacetic acid-   TFAA trifluoroacetic anhydride-   THF tetrahydrofuran-   TPPO triphenylphosphine oxide-   UV ultraviolet spectrometry-   cf. see-   v/v volume to volume ratio (of a solution)

HPLC, GC-MS and LC-MS Methods:

Method 1: instrument: Waters ACQUITY SQD UPLC System; column: WatersAcquity UPLC HSS T3 1.8 μm 50×1 mm; eluent A: 1 l water+0.25 ml 99%formic acid, eluent B: 1 l acetonitrile+0.25 ml 99% formic acid;gradient: 0.0 min 90% A→1.2 min 5% A→2.0 min 5% A; oven: 50° C.; flowrate: 0.40 ml/min; UV detection: 210-400 nm.

Method 2: MS instrument type: Waters (Micromass) Quattro Micro; HPLCinstrument type: Agilent 1100 Serie; column: Thermo Hypersil GOLD 3μ20×4 mm; eluent A: 1 l water+0.5 ml 50% formic acid, eluent B: 1 lacetonitrile+0.5 ml 50% formic acid; gradient: 0.0 min 100% A→3.0 min10% A→4.0 min 10% A→4.01 min 100% A (flow 2.5 ml)→5.00 min 100% A; oven:50° C.; flow rate: 2 ml/min; UV detection: 210 nm.

Method 3: instrument: Micromass Quattro Premier with Waters UPLCAcquity; column: Thermo Hypersil GOLD 1.9 μm 50×1 mm; eluent A: 1 lwater+0.5 ml 50% formic acid, eluent B: 1 l acetonitrile+0.5 ml 50%formic acid; gradient: 0.0 min 90% A→0.1 min 90% A→1.5 min 10% A→2.2 min10% A oven: 50° C.; flow rate: 0.33 ml/min; UV detection: 210 nm.

Method 4: instrument: Micromass Quattro Premier with Waters UPLCAcquity; column: Thermo Hypersil GOLD 1.9 μm 50×1 mm; eluent A: 1 lwater+0.5 ml 50% formic acid, eluent B: 1 l acetonitrile+0.5 ml 50%formic acid; gradient: 0.0 min 97% A→0.5 min 97% A→3.2 min 5% A→4.0 min5% A oven: 50° C.; flow rate: 0.3 ml/min; UV detection: 210 nm.

Method 5 (LC-MS): instrument: Waters ACQUITY SQD UPLC System; column:Waters Acquity UPLC HSS T3 1.8 μm 30×2 mm; eluent A: 1 l water+0.25 ml99% formic acid, eluent B: 1 l acetonitrile+0.25 ml 99% formic acid;gradient: 0.0 min 90% A→1.2 min 5% A→2.0 min 5% A oven: 50° C.; flowrate: 0.60 ml/min; UV detection: 208-400 nm.

Method 6 (GC-MS): instrument: Micromass GCT, GC6890; column: RestekRTX-35, 15 μm×200 μm×0.33 μm; constant flow rate of helium: 0.88 ml/min;oven: 70° C.; inlet: 250° C.; gradient: 70° C., 30° C./min→310° C. (holdfor 3 min).

Method 7 (preparative HPLC): column: Reprosil C18, 10 μm, 250 mm×30 mm.eluent A: formic acid 0.1% in water, eluent B: acetonitrile; flow rate:50 ml/min; program: 0 to 6 min: 90% A/10% B; 6 min to 27 min: gradientto 95% B; 27 min to 38 min 95% B; 38 min to 39 min gradient to 10% B; 39min to 43 min (end): 60% A/40% B. Slight variations in the gradient arepossible.

Method 8 (preparative HPLC): column: Reprosil C18, 10 μm, 250 mm×30 mm.eluent A: formic acid 0.1% in water, eluent B: methanol; flow rate: 50ml/min; program: 0 to 4.25 min: 60% A/40% B; 4.25 to 4.50 min: gradientto 60% B; 4.50 min to 17 min gradient to 100% B; 17 min to 19.50 min100% B; 19.50 min to 19.75 min gradient to 40% B; 19.75 to 22 min (end):60% A/40% B. Slight variations in the gradient are possible.

Method 9 (preparative HPLC): column: Sunfire C18, 5 μm, 250 mm×20 mm.eluent methanol/TFA 1% in water 50/50; flow rate: 25 ml/min; detection210 nm, temperature 40° C.

Method 10 (preparative HPLC): column: Sunfire C18, 5 μm, 250 mm×20 mm.eluent acetonitrile/TFA 1% in water 55/45; flow rate: 25 ml/min;detection 210 nm, temperature 40° C.

Method 11: (preparative HPLC): column: Reprosil C18, 10 μm, 250 mm×40mm. eluent A: formic acid 0.1% in water, eluent B: acetonitrile; flowrate: 50 ml/min. program: 0-6 min: 90% A/10% B; 6-40 min: gradient to95% B; 40-53 min: 5% A/95% B; 53.01-54 min: gradient to 10% B; 54.01-57min: 90% A/10% B.

Method 12 (chiral preparative HPLC): Daicel Chiralpak AD-H 250 mm×20 mmcolumn; flow rate: 20 ml/min; eluent: iso-propanol/ethanol/iso-hexane15:15:70 (v/v/v); detector 230 nm.

Method 13 (chiral analytical HPLC): Daicel Chiralpak AD-H 5 μm column,250 mm×4.6 mm; temperature 30° C.; flow rate: 1 ml/min; eluent:iso-propanol/ethanol/iso-hexane 15:15:70 (v/v/v); detector 220 nm.

Method 14 (chiral analytical HPLC): Daicel Chiralpak AS-H 5 μm column,250 mm×4.6 mm; temperature 30° C.; flow rate: 1 ml/min; eluent:ethanol/iso-hexane 50:50 with addition of 1% water and 0.2%trifluoroacetic acid; detector 220 nm.

Method 15 (preparative HPLC): as Method 7 but with Chromatorex C18 250mm×30 mm column.

Method 16 (chiral preparative HPLC): Daicel Chiralpak AZ-H 250 mm×20 mmcolumn; flow rate: 20 ml/min; eluent: ethanol/iso-hexane 50:50 (v/v)with addition of 1% water and 0.2% trifluoroacetic acid; detector 230nm.

Method 17 (chiral analytical HPLC): Daicel Chiralpak AZ-H 5 μm column,250 mm×4.6 mm; temperature 40° C.; flow rate: 1 ml/min; eluent:ethanol/iso-hexane 50:50 (v/v) with addition of 1% water and 0.2%trifluoroacetic acid; detector 220 nm.

Method 18 (chiral preparative HPLC): Daicel Chiralpak AD-H 250 mm×20 mmcolumn; flow rate: 20 ml/min; eluent: iso-propanol/iso-hexane 50:50(v/v) with addition of 1% water and 0.2% trifluoroacetic acid; detector230 nm.

Method 19 (chiral analytical HPLC): Daicel Chiralpak AD-H 5 μm column,250 mm×4.6 mm; temperature 30° C.; flow rate: 1 ml/min; eluent:iso-propanol/iso-hexane 50:50 (v/v) with addition of 1% water and 0.2%trifluoroacetic acid; detector 220 nm.

Method 20 (chiral preparative HPLC): Daicel Chiralpak AD-H 250 mm×20 mmcolumn; flow rate: 20 ml/min; eluent: ethanol/iso-hexane 70:30 (v/v)with addition of 1% water and 0.2% trifluoroacetic acid; detector 230nm.

Method 21 (chiral analytical HPLC): Daicel Chiralpak AD-H 5 μm column,250 mm×4.6 mm; temperature 40° C.; flow rate: 1 ml/min; eluent:ethanol/iso-hexane 70:30 (v/v) with addition of 1% water and 0.2%trifluoroacetic acid; detector 220 nm.

Method 22 (preparative HPLC): column: Sunfire C18, 5 μm, 250 mm×20 mm.eluent acetonitrile/water 60:40; flow rate: 25 ml/min; detection 210 nm,temperature 40° C.

Method 24 (preparative HPLC): column: Sunfire C18, 5 μm, 75 mm×30 mm.eluent acetonitrile/0.05% TFA in water 1:99 to 2.25 min, thenacetonitrile/1% TFA in water 95:5; flow rate: 60 ml/min; detection 210nm, temperature 40° C.

Method 25 (chiral analytical HPLC): Daicel Chiralpak AD-H 5 μm column,250 mm×4.6 mm; temperature 30° C.; flow rate: 1 ml/min; eluent:iso-propanol/iso-hexane 5:95 (v/v); detector 220 nm.

Method 26: MS, instrument: Thermo Fisher-Scientific DSQ; chemicalionization; reactant gas NH₃; source temperature: 200° C.; ionizationenergy 70 eV.

Method 27 (chiral analytical HPLC): Daicel Chiralpak AD-H 5 μm column,250 mm×4.6 mm; temperature 30° C.; flow rate: 1 ml/min; eluent:iso-propanol/ethanol/iso-hexane 25:25:50 (v/v/v); detector 220 nm.

Method 28 (LC-MS): MCW SQ-HSST3 long instrument: Waters ACQUITY SQD UPLCSystem; column: Waters Acquity UPLC HSS T3 1.8 μm 50×1 mm; eluent A: 1 lwater+0.25 ml 99% formic acid, eluent B: 1 l acetonitrile+0.25 ml 99%formic acid; gradient: 0.0 min 95% A→6.0 min 5% A→7.5 min 5% A; oven:50° C.; flow rate: 0.35 ml/min; UV detection: 210-400 nm.

Method 29 (chiral preparative HPLC): Daicel Chiralpak IC 5 μm column,250 mm×20 mm; flow rate: 20 ml/min; temperature 25° C.; detector: 220nm; eluent: acetonitrile/MTBE 50:50 (v/v).

Method 30 (chiral analytical HPLC): Daicel Chiralpak IC 5 μm column, 250mm×4.6 mm; flow rate: 1 ml/min; temperature 30° C.; detector: 220 nm;eluent: acetonitrile/MTBE 50:50 (v/v).

Method 31 (chiral preparative HPLC): Daicel Chiralpak IA 5 μm column,250 mm×20 mm; flow rate: 20 ml/min; temperature 30° C.; detector: 285nm; eluent: acetonitrile/MTBE 50:50 (v/v).

Method 32 (chiral analytical HPLC): Daicel Chiralpak IA 5 μm column, 250mm×4.6 mm; flow rate: 1 ml/min; temperature 30° C.; detector: 285 nm;eluent: acetonitrile/MTBE 50:50 (v/v).

Method 33 (chiral preparative HPLC): Daicel Chiralpak IA 5 μm column,250 mm×20 mm; flow rate: 20 ml/min; temperature 30° C.; detector: 285nm; eluent: acetonitrile/MTBE 20:80 (v/v).

Method 34 (chiral analytical HPLC): Daicel Chiralpak IA 5 μm column, 250mm×4.6 mm; flow rate: 1 ml/min; temperature 30° C.; detector: 285 nm;eluent: acetonitrile/MTBE 50:50 (v/v).

Starting Compounds and Intermediates Example 1A5-amino-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-one hydrochloride

33.2 g (160 mmol) of1,3-dimethyl-5-nitro-1,3-dihydro-2H-benzimidazol-2-one (preparation: seeWO 2007/120339, Example 2, page 33) in 1790 ml of ethanol (only partlydissolved) were hydrogenated in the presence of 8.8 g of palladiumcatalyst (10% on activated carbon, moistened with 50% water) at RT andhydrogen pressure 1 atm. The starting material dissolved in the courseof the reaction. After completion of conversion (6 h), the catalyst wasremoved by filtration through kieselguhr. The filtrate was admixed with45 ml of a hydrogen chloride solution (4N in dioxane), then concentratedto dryness on a rotary evaporator. The residue was then dried furtherunder HV. This gave 31.8 g (91% of theory) of the title compound.

LC-MS (Method 1): R_(t)=0.18 min; m/z=178 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.33 (s, 3H), 3.34 (s, 3H), 7.06-7.15(m, 2H), 7.23 (d, 1H), 10.29 (br.s, 3H).

Example 2A ethyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

52.80 g (247.1 mmol) of the compound from Example 1A and 64.07 g (247.1mmol) ethyl 3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate (forpreparation see: Senda, Shigeo; Hirota, Kosaku; Notani, Jiyoji, Chemical& Pharmaceutical Bulletin (1972), 20(7), 1380-8) were initially chargedin 2 l of ethanol, and 51.7 ml (370.7 mmol) of triethylamine were added.The thick suspension formed was heated to reflux temperature for 1.5 h,forming a clear solution. After cooling slightly (about 60° C.), 27.73 g(247.1 mmol) of potassium tert-butoxide were added. The reaction mixturewas heated again to reflux temperature and stirred at this temperaturefor a further 7 h. After cooling to RT, about half the solvent wasremoved on a rotary evaporator. The concentrated reaction mixture waspoured into 7.5 l of 1 N hydrochloric acid. The precipitated solid wasfiltered off, washed with 800 ml of water and dried under HV. This gave71.7 g (85% of theory) of the title compound.

LC-MS (Method 1): R_(t)=0.63 min; m/z=345 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 2H), 3.30 (s, 3H), 3.37 (s,3H), 4.17 (q, 2H), 7.19 (dd, 1H), 7.25 (d, 1H), 7.37 (d, 1H), 8.26 (s,1H).

Example 3A1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-benzimidazol-2-one

3.16 g of 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane(12.44 mmol) and 43 mg (70% purity, 0.124 mmol) of dibenzoyl peroxidewere initially charged in 12 ml of acetonitrile at RT, and 1.47 g (8.3mmol) of 5-amino-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-one(prepared as described in Example 1A, except without treatment withhydrogen chloride) and 1.48 ml (12.44 mmol) of tert-butyl nitrite. Thereaction mixture was stirred at RT overnight. The solvent was removed ona rotary evaporator. The residue was dissolved in a littledichloromethane, diatomaceous earth was added to the solution and thesolution was concentrated again to dryness on a rotary evaporator. Theresidue was purified using a silica gel cartridge (eluent:cyclohexane/ethyl acetate 2:1 to 1:1). The product-containing fractionswere concentrated on a rotary evaporator. The residue was stirred with10 ml of pentane, and the precipitated solid was filtered off, washedwith pentane and dried under HV. This gave 860 mg of the title compound(94% purity). Another silica gel chromatography operation with themother liquor gave an additional 230 mg of the title compound (overallyield 43% of theory).

LC-MS (Method 1): R_(t)=0.95 min; m/z=289 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.30 (s, 12H), 3.33 (s, partly underthe water signal), 3.35 (s, 3H), 7.16 (d, 1H), 7.35 (s, 1H), 7.44 (d,1H).

Example 4A 1-(2-chloro-3,6-difluorobenzyl)urea

1.50 g (8.44 mmol) of 2-chloro-3,6-difluorobenzylamine and 2.03 g (33.8mmol) of urea were initially charged in 4 ml of water. After addition of90 μl (approx. 1 mmol) of conc. hydrochloric acid, the reaction mixturewas heated to reflux for 3.5 h. After cooling to RT, 100 ml of waterwere added and the mixture was stirred for 30 min. The precipitatedcrystals were filtered off, washed twice with a little water, then witha little MTBE, and dried under HV. This gave 1.16 g (62% of theory) ofthe title compound.

LC-MS (Method 1): R_(t)=0.79 min; m/z=221 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=4.34 (dd, 2H), 5.51 (s, 2H), 6.36 (t,1H), 7.26-7.34 (m, 1H), 7.39-7.48 (m, 1H).

Example 5A ethyl3-(2-chloro-3,6-difluorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

A suspension of 1.16 g (5.25 mmol) 1-(2-chloro-3,6-difluorobenzyl)ureafrom Example 4A and 1.59 ml (7.86 mmol) of diethylethoxymethylenemalonate in 2 ml of ethanol is heated to 140° C. (bathtemperature) and stirred at this temperature overnight. The reactionmixture cooled to RT was dissolved in about 6 ml of ethanol, 535 mg (7.9mmol) of sodium ethoxide were added and the mixture was again heated toreflux. After 2 days, an additional 0.5 equivalent of base was added andthe mixture was heated to reflux temperature for a further 3 days. Aftercooling to RT, the mixture was acidified with 1M hydrochloric acid andextracted twice with ethyl acetate. The combined organic phases werewashed with a saturated sodium chloride solution, dried over magnesiumsulphate and concentrated on a rotary evaporator. The residue wasstirred with ethyl acetate/MTBE 1:1. The solid was filtered off, washedwith MTBE and dried under HV. This gave 851 mg (45% of theory) of thetitle compound.

LC-MS (Method 1): R_(t)=0.79 min; m/z=345 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 4.16 (q, 2H), 5.13 (s,2H), 7.20-7.29 (m, 1H), 7.38-7.46 (m, 1H), 8.20 (s, 1H), 11.94-12.05 (m,1H).

Example 6A 1-(3-chloro-2-methylbenzyl)urea

The preparation and purification of the title compound were analogous toExample 4A, with a reaction time of 6 h. Proceeding from 2.00 g (12.85mmol) of 3-chloro-2-methylbenzylamine and 3.08 g (51.40 mmol) of urea,this gave 2.36 g (92% of theory) of the title compound.

LC-MS (Method 1): R_(t)=0.72 min; m/z=199 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.29 (s, 3H), 4.19 (d, 2H), 5.53 (s,2H), 6.36 (t, 1H), 7.14-7.22 (m, 2H), 7.28-7.35 (m, 1H).

Example 7A ethyl3-(3-chloro-2-methylbenzyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

A suspension of 2.36 g (11.88 mmol) of 1-(3-chloro-2-methylbenzyl)ureafrom Example 6A and 3.60 ml (17.82 mmol) of diethylethoxymethylenemalonate in 3 ml of ethanol was heated to 140° C. (bathtemperature) and the solution formed after about 3 h was stirred furtherat this temperature overnight. The mixture cooled to RT was dissolved in20 ml of ethanol, 1.21 g (17.8 mmol) of sodium ethoxide were added andthe mixture was again heated to reflux for 1.5 h. After cooling to RT,the reaction mixture was added dropwise to 100 ml of ice-cooled 0.5Mhydrochloric acid. The precipitated solid was filtered off, washed withMTBE and dried under HV. This gave 2.20 g (57% of theory) of the titlecompound.

LC-MS (Method 1): R_(t)=0.90 min; m/z=323 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.24 (t, 3H), 2.40 (s, 3H), 4.17 (q,2H), 4.96 (s, 2H), 6.85 (d, 1H), 7.13 (t, 1H), 7.33 (d, 1H), 8.25 (s,1H), 12.06 (br. s, 1H).

Example 8A 1-[2,3-bis(trifluoromethyl)phenyl]methanamine

Under argon, 69.38 ml (69.38 mmol) of borane-THF complex (1.0M) wereinitially charged and the reaction mixture was cooled to 0° C.Subsequently, a solution of 5.53 g (23.13 mmol) of2,3-bis(trifluoromethyl)-benzonitrile (for preparation see: ZhurnalOrganicheskoi Khimii 1973, 9(5), 1019-1024, 1046-1050) in 50 ml of THFand heated to reflux for 3 h. The reaction mixture was cooled to 0° C.,acidified with 1N hydrochloric acid and concentrated under reducedpressure. The residue was diluted with water and the aqueous phase waswashed three times with dichloromethane. Subsequently, 1N sodiumhydroxide solution was used to adjust the pH to 14, the mixture wasextracted three times with dichloromethane and the combined organicphases were dried over sodium sulphate, filtered and concentrated. Thisgave 4.07 g (70% of theory) of the title compound.

LC-MS (Method 1): R_(t)=0.49 min; MS (ESIpos): m/z=244 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.99 (br.s, 2H), 3.90-3.97 (m, 2H),7.83-7.92 (m, 2H), 8.17-8.23 (m, 1H).

Example 9A 1-[2,3-bis(trifluoromethyl)benzyl]urea

780 mg (3.21 mmol) of 1-[2,3-bis(trifluoromethyl)phenyl]methanamine fromExample 8A and 771 mg (12.83 mmol) of urea were initially charged in 1.3ml of water, 34 μl (0.41 mmol) of conc. hydrochloric acid were addeddropwise and the mixture was heated to reflux for 3 h. This was followedby dilution with water (100 ml) at RT and stirring for 30 min. The solidformed was filtered off, washed twice each with water and diethyl ether,and dried under high vacuum. This gave 541 mg (59% of theory) of thetarget compound.

LC-MS (Method 1): R_(t)=0.85 min; MS (ESIpos): m/z=287 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=4.40-4.45 (m, 2H), 5.72 (s, 2H),6.57-6.63 (m, 1H), 7.86-7.90 (m, 2H), 7.91-7.95 (m, 1H).

Example 10A ethyl3-[2,3-bis(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

A mixture of 2.01 g (7.04 mmol) of1-[2,3-bis(trifluoromethyl)benzyl]urea from Example 9A and 2.13 ml(10.60 mmol) of diethyl (ethoxymethylene)malonate was stirred in anopposing argon flow at 140° C. for 4 days. The reaction mixture wassubsequently diluted with ethanol (20 ml), then 0.72 g (10.60 mmol) ofsodium ethoxide was added and the mixture was heated to reflux for afurther 2.5 h. The mixture brought to RT was added dropwise toice-cooled hydrochloric acid (400 ml, 0.5M) and the solid formed wasfiltered off. The filter residue was stirred with MTBE, filtered off anddried under high vacuum. This gave 1.92 g (67% of theory) of the targetcompound.

LC-MS (Method 1): R_(t)=0.99 min; MS (ESIpos): m/z=411 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.24 (t, 3H), 4.18 (q, 2H), 5.17(br.s, 2H), 7.52 (d, 1H), 7.76-7.83 (m, 1H), 7.92-7.98 (m, 1H), 8.29 (s,1H), 12.15 (br.s, 1H).

Example 11A N-benzyl-4-(trifluoromethyl)indan-1-amine (racemate)

To a mixture of 15.40 g (0.075 mol) of 4-(trifluoromethyl)-1-indanoneand 9.78 ml (0.090 mol) of benzylamine in 462 ml of dichloromethane wereadded 33.0 ml (0.112 mol) of titanium(IV) isopropoxide and the mixturewas stirred at RT for 1 h. Subsequently, at 0° C., 5.65 g (0.149 mol) ofsodium borohydride were added in portions and the mixture was stirred atRT overnight. For workup, the mixture was subsequently added dropwise towater with vigorous evolution of gas. Thereafter, the mixture wasdiluted further with water and dichloromethane (500 ml of each), theorganic phase was dried over sodium sulphate and filtered, and thefiltrate was concentrated. The crude product thus obtained waschromatographed on silica gel (petroleum ether/ethyl acetate, 10:1).This gave 12.80 g (58% of theory) of the target compound.

LC-MS (Method 1): R_(t)=0.80 min; MS (ESIpos): m/z=292 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.81-1.93 (m, 1H), 2.31-2.42 (m, 1H),2.57-2.65 (m, 1H), 2.81-2.93 (m, 1H), 3.04-3.15 (m, 1H), 3.72-3.85 (m,2H), 4.14-4.22 (m, 1H), 7.19-7.25 (m, 1H), 7.32 (t, 2H), 7.37-7.44 (m,3H), 7.53 (d, 1H), 7.68 (d, 1H).

Example 12A 4-(trifluoromethyl)indan-1-amine (racemate)

9.70 g (0.032 mol) of N-benzyl-4-(trifluoromethyl)indan-1-amine fromExample 11A were initially charged in 230 ml of THF, then 5.00 g ofpalladium (10% on activated carbon) were added and the mixture at RT washydrogenated at RT under standard hydrogen pressure overnight.Subsequently, the mixture was filtered through kieselguhr and thefiltrate was concentrated. This gave 6.40 g (98% of theory) of crudeproduct, which was converted without further purification.

LC-MS (Method 1): R_(t)=0.56 min; MS (ESIpos): m/z=202 (M+H)⁺.

Example 13A 1-[4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]urea(racemate)

6.40 g (0.03 mol) of 4-(trifluoromethyl)indan-1-amine from Example 12Aand 9.55 g (0.159 mol) of urea were initially charged in 25 ml of water,0.34 ml (0.004 mol) of conc. hydrochloric acid were added dropwise andthe mixture was heated to reflux for 3 h. The mixture was diluted withwater (100 ml) at RT and stirred for 30 min. The solid formed wasfiltered off, washed with water and dried under high vacuum. The crudeproduct was recrystallized by stirring with diethyl ether (50 ml). Thisgave 4.60 g (59% of theory) of the target compound.

LC-MS (Method 1): R_(t)=0.83 min; MS (ESIpos): m/z=245 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.71-1.82 (m, 1H), 2.39-2.49 (m, 1H),2.84-2.96 (m, 1H), 3.00-3.11 (m, 1H), 5.12 (q, 1H), 5.53 (s, 2H), 6.42(d, 1H), 7.39-7.45 (m, 1H), 7.53 (dd, 2H).

Example 14A (S)-4-trifluoromethylindan-1-ol

A solution of 55.7 g (278.3 mmol) of 4-trifluoromethyl-1-indanone, 194ml (1.391 mol) of triethylamine and 1.60 g (2.50 mmol) ofRuCl(p-cymene)[(S,S)-TsDPEN](CAS No.: 192139-90-5; IUPAC name:(S,S)—N-(p-toluenesulphonyl)-1,2-diphenylethanediamino(chloro)[1-methyl-4-(propan-2-yl)benzene]ruthenium(II))in 258 ml of dichloromethane was heated to 35° C. under argon and, atthis temperature, 52.5 ml (1.391 mol) of formic acid were addedgradually (addition time about 40 min). In the course of this, thetemperature of the reaction mixture rose to 42° C. On completion ofaddition, the mixture was stirred at 38° C. for a further 2 h. Allvolatile constituents were removed on a rotary evaporator and under HV.Subsequently, the residue was dissolved in a little dichloromethane andpurified using 1 kg of silica gel (eluent: first 3 litres ofcyclohexane/ethyl acetate 5:1, then 6 litres of cyclohexane/ethylacetate 1:1). The suitable fractions were concentrated on a rotaryevaporator and the product was dried under HV. This gave 51.2 g (90% oftheory) of the title compound.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.76-1.91 (m, 1H), 2.40 (ddt, 1H),2.86 (dt, 1H), 3.01-3.13 (m, 1H), 5.09 (q, 1H), 5.45 (d, 1H), 7.38-7.48(m, 1H), 7.55 (d, 1H), 7.62 (d, 1H).

Chiral analytical HPLC (Method 25): R_(t)=7.49 min; 99% ee

Example 15A (R)-4-trifluoromethylindan-1-ol

Analogously to Example 14A, 5 g (25.0 mmol) of4-trifluoromethyl-1-indanone were reduced in the presence of 143 mg(0.225 mmol) of RuCl(p-cymene)[(R,R)-TsDPEN](CAS No.: 192139-92-7; IUPACname:(R,R)—N-(p-toluenesulphonyl)-1,2-diphenylethanediamino(chloro)[1-methyl-4-(propan-2-yl)benzene]ruthenium(II)).This gave 4.60 g (91% of theory) of the title compound.

GC-MS (Method 6): R_(t)=3.43 min; MS (CI-pos): m/z=202 (M)⁺.

¹H NMR (400 MHz, CDCl₃): δ [ppm]=1.94 (br d, 1H), 1.96-2.05 (m, 1H),2.55 (dddd, 1H), 2.91-3.04 (m, 1H), 3.19-3.30 (m, 1H), 5.27 (q, 1H),7.32-7.38 (m, 1H), 7.53 (d, 1H), 7.60 (d, 1H).

Chiral analytical HPLC (Method 25): R_(t)=6.51 min; ee approx. 96%.

Example 16A 5-amino-1-methyl-1,3-dihydro-2H-benzimidazol-2-one

2.43 g (12.6 mmol) of 1-methyl-5-nitro-1,3-dihydro-2H-benzimidazol-2-one[synthesis described in U.S. Pat. No. 6,114,532] were initially chargedin 78.0 ml of a THF/methanol mixture (1:2), then 134 mg (0.13 mmol) ofpalladium (10% on activated carbon) were added and the mixture washydrogenated at standard hydrogen pressure overnight. Subsequently, thereaction mixture was filtered through kieselguhr, the residue was washedwith THF and the filtrate was concentrated. This gave 1.89 g (92% oftheory) of the target compound.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.16 (s, 3H), 4.66-4.71 (m, 2H), 6.25(dd, 1H), 6.28 (d, 1H), 6.71 (d, 1H), 10.39 (s, 1H).

Example 17A 5-fluoro-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-one

Under argon, 5.0 ml of DMF were initially charged at 0° C. and 318 mg(7.96 mmol) of sodium hydride (60% suspension in mineral oil) wereadded. Subsequently, a solution of 881 mg (5.30 mmol) of5-fluoro-1-methyl-1,3-dihydro-2H-benzimidazol-2-one [synthesis describedin US 2010/0305102, page 28, Example 26.3] in 5.0 ml of DMF was addeddropwise and the reaction mixture was stirred for 30 min. Thereafter,0.43 ml (6.90 mmol) of iodomethane was added dropwise and the mixturewas stirred at RT overnight. Subsequently, sodium hydride (1.0 eq) wasagain added at 0° C., the mixture was stirred for a further 15 min andfinally iodomethane (1.0 eq) was added dropwise. The reaction mixturewas stirred at RT for 2 h, then water (100 ml) was added and the mixturewas extracted with ethyl acetate (3×50 ml). The combined organic phaseswere washed with water and saturated sodium chloride solution, driedover magnesium sulphate and filtered, and the filtrate was concentrated.The crude product thus obtained was purified by means of flash silicagel chromatography (cyclohexane/ethyl acetate, gradient 7:1-4:1). Thisgave 672 mg (69% of theory) of the target compound.

LC-MS (Method 1): R_(t)=0.69 min; MS (ESIpos): m/z=181 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.33 (s, 3H), 3.3 (s, concealed bywater signal), 6.85-6.93 (m, 1H), 7.09-7.18 (m, 2H).

Example 18A5-fluoro-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzimidazol-2-one

670 mg (3.72 mmol) of5-fluoro-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-one from Example 17Awere initially charged in 3.5 ml of THF under argon at 0° C. Thereafter,0.24 ml (3.72 mmol) of nitric acid (65%) was added dropwise and themixture was stirred at 0° C. for 1 h. Subsequently, the reaction mixturewas added to ice-water (50 ml), and the solid formed was filtered off,washed with water (20 ml) and then dried at 40° C. under high vacuum.This gave 807 mg (92% of theory) of the target compound, which wasconverted without further purification.

LC-MS (Method 1): R_(t)=0.70 min; MS (ESIpos): m/z=226 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.38 (s, 3H), 3.40 (s, 3H), 7.52 (d,1H), 7.99 (d, 1H).

Example 19A5-amino-6-fluoro-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-one

806 mg (3.58 mmol) of5-fluoro-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzimidazol-2-one fromExample 18A were initially charged in 22.2 ml of a THF/methanol mixture(1:2), then 38 mg (0.04 mmol) of palladium (10% on activated carbon)were added and the mixture was hydrogenated at standard hydrogenpressure overnight. Subsequently, the reaction mixture was filteredthrough kieselguhr, the residue was washed with methanol, and thefiltrate was concentrated and dried under high vacuum. This gave 668 mg(85% purity, 81% of theory) of the target compound, which was convertedwithout further purification.

LC-MS (Method 1): R_(t)=0.43 min; MS (ESIpos): m/z=196 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.21 (s, 3H), 3.22 (s, 3H), 4.78(br.s, 2H), 6.53 (d, 1H), 6.98 (d, 1H).

Example 20A5-amino-3-hydroxy-1-methyl-3-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one

2.45 g (8.87 mmol) of3-hydroxy-1-methyl-5-nitro-3-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one[for preparation see: Journal of Heterocyclic Chemistry, 2008, 45, 4, p.969-973] were initially charged in 20.0 ml of ethanol, then 600 mg ofpalladium (10% on activated carbon) were added and the mixture washydrogenated at standard hydrogen pressure for 4 h. Subsequently, thereaction mixture was filtered through kieselguhr, the residue was washedwith methanol (30 ml) and the filtrate was concentrated. This gave 2.06g (91% of theory) of the target compound.

LC-MS (Method 2): R_(t)=0.97 min; MS (ESIpos): m/z=247 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.07 (s, 3H), 4.97-5.33 (m, 2H), 6.64(dd, 1H), 6.77-6.81 (m, 2H), 7.51 (s, 1H).

Example 21A ethyl2,4-dioxo-3-[4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate)

A mixture of 5.2 g (20 mmol) of1-[4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]urea from Example 13Aand 8.26 ml (41 mmol) of diethyl (ethoxymethylene)malonate was heated toreflux at 140° C. for 24 h (barely stirrable at the start, thenhomogeneous and stirrable). After cooling to RT, 47.7 ml of ethanol and2.78 g (41 mmol) of sodium ethoxide were added and the mixture washeated to reflux for a further 24 h. For workup, the reaction mixturewas concentrated under reduced pressure, acidified with 1M hydrochloricacid (80 ml) and extracted three times with 80 ml each time of ethylacetate. The combined organic phases were dried over sodium sulphate andfiltered, and the filtrate was concentrated. The residue waschromatographed on silica gel (petroleum ether/ethyl acetate 3:1 to1:3). This gave 4.20 g (56% of theory) of the title compound.

LC-MS (Method 1): R_(t)=0.94 min; MS (ESIpos): m/z=369 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 2.27-2.38 (m, 1H),2.39-2.49 (m, 1H), 3.01-3.13 (m, 1H), 3.23-3.32 (m, 1H), 4.10-4.22 (m,2H), 6.29-6.46 (m, 1H), 7.29-7.39 (m, 2H), 7.52 (d, 1H), 8.13-8.20 (m,1H), 11.74-11.99 (m, 1H).

Example 22A ethyl1-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

1.00 g (4.13 mmol) of5-amino-1,3-diethyl-1,3-dihydro-2H-benzimidazol-2-one hydrochloride,0.63 ml (4.55 mmol) of triethylamine and 1.07 g (4.13 mmol) of ethyl3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate (for preparation see:Senda, Shigeo; Hirota, Kosaku; Notani, Jiyoji, Chemical & PharmaceuticalBulletin (1972), 20(7), 1380-8) were initially charged in 31 ml ofethanol and the mixture was heated to reflux for 2 h. Subsequently, 464mg (4.13 mmol) of potassium tert-butoxide were added at RT and thereaction mixture was stirred at RT overnight. Thereafter, the reactionmixture was heated to reflux for a further 3 h. For workup, water wasadded at RT and the mixture was acidified with 1N hydrochloric acid. Theprecipitated solid was filtered off with suction, washed once each withwater and ethyl acetate, and dried under reduced pressure at 50° C. Thisgave 783 mg (51% of theory) of the target compound.

LC-MS (Method 3): R_(t)=0.84 min; MS (ESIpos): m/z=373 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.18-1.26 (m, 9H), 3.83-3.95 (m, 4H),4.17 (q, 2H), 7.18 (dd, 1H), 7.31 (d, 1H), 7.44 (d, 1H), 8.30 (s, 1H),11.68 (s, 1H).

Example 23A1-methyl-5-nitro-3-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-benzimidazol-2-one

8.00 g (41.4 mmol) of 1-methyl-5-nitro-1,3-dihydro-2H-benzimidazol-2-one[synthesis described in U.S. Pat. No. 6,114,532] were initially chargedtogether with 11.45 g (82.8 mmol) of potassium carbonate in 600 ml ofacetonitrile/DMF 2:1 (v/v), and 7.48 ml (45.6 mmol) of2,2,2-trifluoroethyl trichloromethanesulphonate were added. The reactionmixture was heated to reflux temperature and stirred at this temperatureovernight. After cooling to RT, the mixture was poured into 1.8 l of0.1N hydrochloric acid. The precipitated solid was filtered off anddried under HV. This gave 11.3 g (97% of theory) of the title compound.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.44 (s, 3H), 4.97 (q, 2H), 7.44 (d,1H), 8.14 (dd, 1H), 8.33 (d, 1H).

Example 24A5-amino-1-methyl-3-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-benzimidazol-2-one

11.3 g (41.06 mmol) of the compound from Example 23A were initiallycharged in 623 ml of methanol/tetrahydrofiuran 2:1 (v/v). 1.66 g ofpalladium on carbon (10% on carbon) and 25.9 g (410.6 mmol) of ammoniumformate were added and the reaction mixture was stirred at 70° C. for 4h. After cooling to RT, the catalyst was filtered off and the filtratewas freed of the solvents on a rotary evaporator. The residue wasadmixed with 100 ml of a saturated sodium hydrogencarbonate solution and400 ml of water. The solid formed was filtered off, washed with 50 ml ofwater and dried under HV. This gave 8.90 g (86% of theory) of the titlecompound.

LC-MS (Method 5): R_(t)=0.41 min; m/z=246 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.25 (s, 3H), 4.63 (q, 2H), 4.89 (br.s, 2H), 6.37 (dd, 1H), 6.48 (s, 1H), 6.85 (d, 1H).

Example 25A ethyl1-[1-methyl-2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzimidazol-5-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

8.90 g (36.3 mmol) of the compound from Example 24A and 9.41 g (36.3mmol) of ethyl 3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate (forpreparation see: Senda, Shigeo; Hirota, Kosaku; Notani, Jiyoji, Chemical& Pharmaceutical Bulletin (1972), 20(7), 1380-8) were heated to refluxtemperature in 784 ml of ethanol for 1.5 h. After cooling slightly(about 60° C.), 4.07 g (36.3 mmol) of potassium tert-butoxide wereadded. The reaction mixture was heated again to reflux temperature for30 min. After cooling to RT, the reaction mixture was poured into 5 l ofice-cooled 1N hydrochloric acid. The precipitated solid was filteredoff, washed with 800 ml of water and dried under HV. This gave 12.7 g(83% of theory) of the title compound.

LC-MS (Method 1): R_(t)=0.70 min; m/z=413 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 3.40 (s, 3H), 4.17 (q,2H), 4.78 (q, 2H), 7.25-7.30 (m, 1H), 7.31-7.36 (m, 1H), 7.52 (s, 1H),8.26 (s, 1H), 11.71 (s, 1H).

Example 26A ethyl2,4-dioxo-1-(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The target compound was prepared analogously to Example 25A using 1.00 g(6.71 mmol) of 5-amino-1,3-dihydro-2H-benzimidazol-2-one and 1.74 g(6.71 mmol) of ethyl 3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate.This gave 1.60 g (75% of theory) of the target compound.

LC-MS (Method 1): R_(t)=0.46 min; MS (ESIpos): m/z=317 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 4.16 (q, 2H), 6.97-7.04(m, 2H), 7.07-7.10 (m, 1H), 8.23 (s, 1H), 10.84-10.90 (m, 2H), 11.61 (s,1H).

Example 27A ethyl1-(6-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

1.59 g (6.13 mmol) of ethyl3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate (for preparation see:Senda, Shigeo; Hirota, Kosaku; Notani, Jiyoji, Chemical & PharmaceuticalBulletin (1972), 20(7), 1380-8) and 1.00 g (6.13 mmol) of5-amino-6-methyl-1,3-dihydro-2H-benzimidazol-2-one were heated to refluxin 46 ml of ethanol for 2 h. Thereafter, 0.69 g (6.13 mmol) of potassiumtert-butoxide were added at RT and the reaction mixture was stirred atRT overnight and at reflux for 1 h. For workup, the reaction mixture wasadmixed with water and acidified with 1N hydrochloric acid. The solidformed was filtered off, washed with water and ethyl acetate, and thendried under reduced pressure at 50° C. This gave 1.46 g (72% of theory)of the target compound.

LC-MS (Method 1): R_(t)=0.52 min; MS (ESIpos): m/z=331 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 2.08 (s, 3H), 4.16 (q,2H), 6.89 (s, 1H), 7.03 (s, 1H), 8.19 (s, 1H), 10.77 (s, 1H), 10.78 (s,1H), 11.65 (s, 1H).

Example 28A ethyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

40.0 g (243.7 mmol) of 6-amino-3-methyl-1,3-benzoxazol-2(3H)-one wereinitially charged in 2.5 l of ethanol, and 63.2 g (243.7 mmol) ethyl3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate (for preparation see:Senda, Shigeo; Hirota, Kosaku; Notani, Jiyoji, Chemical & PharmaceuticalBulletin (1972), 20(7), 1380-8) were added. After a few minutes, a thicksuspension formed. This mixture was heated to reflux temperature for 1.5h. After cooling slightly (about 60° C.), 27.3 g (243.7 mmol) ofpotassium tert-butoxide were added and the reaction mixture was stirredfurther at reflux temperature for 4.5 h. For workup, the reactionsuspension was cooled slightly (about 60° C.), then stirred into about10 litres of cold 1N hydrochloric acid. The solid was filtered off withsuction, washed with water and dried in a vacuum drying cabinet at 70°C. overnight. This gave 64.0 g (79% of theory) of the title compound.

LC-MS (Method 1): R_(t)=0.59 min; MS (ESIpos): m/z=332 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 3.38 (s, 3H), 4.17 (q,2H), 7.38 (s, 2H), 7.59 (s, 1H), 8.26 (s, 1H), 11.69 (s, 1H).

Example 29A 6-amino-3-ethyl-1,3-benzoxazol-2(3H)-one

1.00 g (4.80 mmol) of 3-ethyl-6-nitro-1,3-benzoxazol-2(3H)-one [forpreparation see: WO 2007/120339 A1, 37-38] was initially charged in 32.5ml of ethanol, then 51 mg (0.05 mmol) of palladium (10% on activatedcarbon) were added and the mixture was hydrogenated at standard hydrogenpressure overnight. Subsequently, the reaction mixture was filteredthrough kieselguhr and the filtrate was concentrated. The residue wastaken up in 50.0 ml of an ethanol/THF mixture (1:1), 50 mg (0.05 mmol)of palladium (10% on activated carbon) were added and the mixture washydrogenated further at standard hydrogen pressure overnight. Thereaction mixture was filtered again through kieselguhr, the filtercakewas washed with ethanol and the filtrate was concentrated. The residuewas subjected to extractive stirring in ethanol, and the solid wasfiltered off and washed with ethanol. After drying under high vacuum,this gave 747 mg of the target compound (83% of theory).

LC-MS (Method 3): R_(t)=0.29 min; MS (ESIpos): m/z=179 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.21 (t, 3H), 3.74 (q, 2H), 4.99-5.05(m, 2H), 6.42 (dd, 1H), 6.55 (d, 1H), 6.94 (d, 1H).

Example 30A ethyl1-(3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

746 mg (4.19 mmol) of 6-amino-3-ethyl-1,3-benzoxazol-2(3H)-one fromExample 29A and 1.09 g (4.19 mmol) of ethyl3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate were initially charged in32 ml of ethanol and the mixture was heated to reflux for 2 h. Aftercooling to RT, 470 mg (4.19 mmol) of potassium tert-butoxide were addedand the reaction mixture was stirred further at RT overnight.Subsequently, the mixture was heated to reflux for 1 h. For workup, thereaction mixture was admixed with water at RT and acidified with 1Mhydrochloric acid. The solid formed was filtered off, washed with waterand ethyl acetate/MTBE (1:1) and dried at 50° C. under reduced pressureovernight. This gave 951 mg (66% of theory) of the target compound.

LC-MS (Method 1): R_(t)=0.71 min; MS (ESIpos): m/z=346 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 1.28 (t, 3H), 3.90 (q,2H), 4.17 (q, 2H), 7.36-7.41 (m, 1H), 7.43-7.47 (m, 1H), 7.59-7.62 (m,1H), 8.28 (s, 1H), 11.70 (s, 1H).

Example 31A ethyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

450 mg (2.50 mmol) of 6-amino-3-methyl-1,3-benzothiazol-2(3H)-one (J.Het. Chem. 1992, 29 (5), 1069-1076, Example 8b) and 647 mg (2.50 mmol)of ethyl 3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate were initiallycharged in 19 ml of ethanol and the mixture was heated to reflux for 2h. After cooling to RT, 280 mg (2.50 mmol) of potassium tert-butoxidewere added and the reaction mixture was stirred further at RT overnight.For workup, the reaction mixture was diluted with water and acidifiedwith 1M hydrochloric acid, and the solid formed was filtered off. Thesolid was washed with water and ethyl acetate, and dried under reducedpressure at 50° C. overnight. This gave 736 mg (85% of theory) of thetarget compound.

LC-MS (Method 1): R_(t)=0.70 min; MS (ESIpos): m/z=348 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 3.45 (s, 3H), 4.17 (q,2H), 7.42-7.47 (m, 1H), 7.51-7.55 (m, 1H), 7.83-7.86 (m, 1H), 8.32 (s,1H), 11.71 (s, 1H).

Example 32A 1-methyl-6-nitro-1,3-dihydro-2H-benzimidazol-2-one

500 mg (2.99 mmol) of N²-methyl-4-nitrobenzene-1,2-diamine [synthesisdescribed in WO 2008/128009, page 49] were initially charged in DMF (9ml), then 4.17 ml (0.73 mmol) of triethylamine and 2.42 g (15.0 mmol) ofN,N′-carbonyldiimidazole were added and the mixture was stirred at 100°C. for 5 h. Subsequently, the reaction mixture was admixed with waterand adjusted to pH 3 with 1M hydrochloric acid. The solid formed wasfiltered off, washed with water and dried at 50° C. under reducedpressure overnight. This gave 482 mg (91% purity, 76% of theory) of thetarget compound. The crude product was converted without furtherpurification.

LC-MS (Method 3): R_(t)=0.71 min; MS (ESIpos): m/z=194 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.37 (s, 3H), 7.15 (d, 1H), 7.97-8.01(m, 1H), 8.02-8.03 (m, 1H), 11.64 (s, 1H).

Example 33A 6-amino-1-methyl-1,3-dihydro-2H-benzimidazol-2-one

480 mg (2.49 mmol) of the nitro compound from Example 32A were initiallycharged in 31 ml of ethanol, then 132 mg (0.12 mmol) of palladium (10%on activated carbon) were added and the mixture was hydrogenated atstandard hydrogen pressure for 2 h. Subsequently, the reaction mixturewas filtered through kieselguhr, the residue was washed with methanoland the filtrate was concentrated. This gave 418 mg (90% purity, 93% oftheory) of the target compound. The crude product was converted withoutfurther purification.

LC-MS (Method 2): R_(t)=0.27 min; MS (ESIpos): m/z=164 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.16 (s, 3H), 4.72 (s, 2H), 6.23 (dd,1H), 6.28-6.31 (m, 1H), 6.63 (d, 1H), 10.28 (s, 1H).

Example 34A ethyl1-(3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

410 mg (2.51 mmol) of 6-amino-1-methyl-1,3-dihydro-2H-benzimidazol-2-onefrom Example 33A and 651 mg (2.51 mmol) of ethyl(2E)-3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate [for preparationsee: Senda, Shigeo; Hirota, Kosaku; Notani, Jiyoji, Chemical &Pharmaceutical Bulletin (1972), 20(7), 1380-1388] were initially chargedin 19 ml of ethanol and the mixture was heated to reflux for 2 h.Subsequently, 282 mg (2.51 mmol) of potassium tert-butoxide were addedat RT and the mixture was heated to reflux for a further 3 h. Forworkup, the reaction mixture was admixed with water and acidified to pH3 with 1N hydrochloric acid. The solid formed was filtered off withsuction, washed with ethyl acetate and dried under reduced pressure at50° C. This gave 251 mg (73% purity, 22% of theory) of the targetcompound, which were converted without further purification. Theremaining filtrate was extracted three times with ethyl acetate, and thecombined organic phases were dried over magnesium sulphate, filtered andconcentrated. The residue was subjected to extractive stirring in ethylacetate/MTBE mixture, and the solid was filtered off and dried underhigh vacuum. This gave a further 443 mg (53% of theory) of the targetcompound.

LC-MS (Method 1): R_(t)=0.51 min; MS (ESIpos): m/z=331 (M+H)⁺.

Example 35A 5-amino-1-methyl-1,3-dihydro-2H-benzimidazol-2-one

29.5 g (150 mmol) of 1-methyl-5-nitro-1,3-dihydro-2H-benzimidazol-2-one[synthesis described in U.S. Pat. No. 6,114,532] were initially chargedin 630 ml of methanol and 315 ml of THF, 1.62 g of palladium (10% onactivated carbon) were added and the mixture was hydrogenated understandard hydrogen pressure at RT. At the end of the reaction, thereaction mixture was filtered through kieselguhr and the filtrate wasconcentrated on a rotary evaporator. The residue was stirred withdiethyl ether, filtered off with suction and dried. This gave 24.5 g(96% of theory) of the title compound.

LC-MS (Method 1): R_(t)=0.16 min; MS (ESIpos): m/z=164 (M+H)⁺.

Example 36A ethyl1-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

5.00 g (29.3 mmol) of 5-amino-1-methyl-1,3-dihydro-2H-benzimidazol-2-onefrom Example 35A and 7.60 g (29.3 mmol) of ethyl3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate were heated to reflux in250 ml of ethanol for 2 h. After cooling to RT, 3.29 g (29.3 mmol) ofpotassium tert-butoxide were added and the reaction mixture was heatedto reflux for a further 2.5 h. For workup, the reaction mixture wasacidified at RT with 4M hydrochloric acid and diluted with water. Themixture was partly concentrated under reduced pressure and the remainingsuspension was filtered. The filter residue was washed with water andethyl acetate, and dried under reduced pressure at 30° C. This gave 7.56g (78% of theory) of the target compound.

LC-MS (Method 5): R_(t)=0.52 min; MS (ESIpos): m/z=331 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 3.31 (s, 3H), 4.16 (q,2H), 7.10-7.21 (m, 3H), 8.23 (s, 1H), 11.12 (s, 1H), 11.63 (s, 1H).

Example 37A N-[4-(cyclobutylamino)-3-nitrophenyl]acetamide

1.00 g (5.04 mmol) N-(4-fluoro-3-nitrophenyl)acetamide (for preparationsee: WO2005/72741 page 26, Example 117A) and 0.86 ml (10.09 mmol) ofcyclobutylamine were initially charged in 40 ml of ethanol, then 1.40 ml(10.09 mmol) of triethylamine were added and the reaction mixture wasstirred in a microwave at 140° C. for 1.5 h. For workup, the mixture wasconcentrated under reduced pressure, the residue was stirred with MTBE,and the solid formed was filtered off and dried under high vacuum. Thisgave 185 mg (69% purity, 10% of theory) of the target compound. Theremaining filtrate was concentrated, and the residue was taken up inethyl acetate, washed once each with water and saturated sodium chloridesolution, dried over magnesium sulphate, filtered and concentrated.After drying under high vacuum, this gave a further 1.01 g (78% oftheory) of the target compound.

LC-MS (Method 3): R_(t)=1.31 min; MS (ESIpos): m/z=250 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.70-1.85 (m, 2H), 1.93-2.04 (m, 5H),2.39-2.47 (m, 2H), 4.12 (sxt, 1H), 6.92 (d, 1H), 7.65 (dd, 1H), 7.93 (d,1H), 8.46 (d, 1H), 9.97 (s, 1H).

Example 38A N-[3-amino-4-(cyclobutylamino)phenyl]acetamide

1.02 g (4.07 mmol) N-[4-(cyclobutylamino)-3-nitrophenyl]acetamide fromExample 37A were initially charged in 96 ml of ethyl acetate, then 216mg (0.20 mmol) of palladium (10% on activated carbon) were added and themixture was hydrogenated at standard hydrogen pressure for 2 h.Subsequently, the reaction mixture was filtered through kieselguhr, theresidue was washed with methanol and the filtrate was concentrated. Thisgave 870 mg (90% purity, 87% of theory) of the title compound. The crudeproduct was converted without further purification.

LC-MS (Method 2): R_(t)=1.01 min; MS (ESIpos): m/z=220 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.64-1.87 (m, 4H), 1.93 (s, 3H),2.28-2.38 (m, 2H), 3.76 (sxt, 1H), 4.42 (d, 1H), 4.51-4.60 (m, 2H), 6.20(d, 1H), 6.61 (dd, 1H), 6.82 (d, 1H), 9.34 (s, 1H).

Example 39A N-(1-cyclobutyl-1H-benzimidazol-5-yl)acetamide

870 mg (3.96 mmol) of N-[3-amino-4-(cyclobutylamino)phenyl]acetamidefrom Example 38A were initially charged in 25 ml of(diethoxymethoxy)ethane, then 0.43 ml (5.17 mmol) of conc. hydrochloricacid were added dropwise and the reaction mixture was stirred at RTovernight. The precipitated solid was filtered off with suction, washedwith ethyl acetate and dried under high vacuum. This gave 930 mg (100%of theory) of the title compound.

LC-MS (Method 1): R_(t)=0.43 min; MS (ESIpos): m/z=230 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.89-2.00 (m, 2H), 2.11 (s, 3H),2.57-2.64 (m, 4H), 5.15 (quin, 1H), 7.59-7.64 (m, 1H), 7.86 (d, 1H),8.38 (d, 1H), 9.66 (s, 1H), 10.53 (s, 1H).

Example 40A 1-cyclobutyl-1H-benzimidazol-5-amine

920 mg (4.01 mmol) of N-(1-cyclobutyl-1H-benzimidazol-5-yl)acetamidefrom Example 39A were initially charged in 20 ml of a 1:1 mixture of 1Mhydrochloric acid and ethanol, and the reaction mixture was stirred at120° C. for 1 h. The reaction mixture cooled to RT was concentrated,taken up in ethyl acetate, washed once each with 1N sodium hydroxidesolution and saturated sodium chloride solution, and the organic phasewas dried over magnesium sulphate, filtered and concentrated underreduced pressure. This gave 593 mg (75% of theory) of the titlecompound.

LC-MS (Method 2): R_(t)=0.89 min; MS (ESIpos): m/z=189 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.80-1.92 (m, 2H), 2.43-2.48 (m,partly concealed by DMSO signal), 4.66-4.76 (m, 2H), 4.82 (quin, 1H),6.59 (dd, 1H), 6.76 (d, 1H), 7.24 (d, 1H), 8.07 (s, 1H).

Example 41A ethyl1-(1-cyclobutyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the target compound were analogousto Example 27A, with a reaction time of 3 h under reflux. Proceedingfrom 590 mg (3.15 mmol) of 1-cyclobutyl-1H-benzimidazol-5-amine fromExample 40A and 817 mg (3.15 mmol) of ethyl3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate, 832 mg (67% of theory)of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.62 min; MS (ESIpos): m/z=355 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.18 (t, 3H), 1.86-1.97 (m, 2H),2.55-2.58 (m, partly concealed by DMSO signal), 3.40-3.48 (m, 1H), 4.06(q, 2H), 5.01 (quin, 1H), 7.16 (dd, 1H), 7.54 (d, 1H), 7.62 (d, 1H),7.96 (s, 1H), 8.45 (s, 1H).

Example 42A N-ethyl-2,4-dinitroaniline

2.00 g (9.87 mmol) of 1-chloro-2,4-dinitrobenzene were initially chargedin 20 ml of THF, then, at 0° C., 5.92 ml (11.84 mmol) of a 2M solutionof ethylamine in THF were added dropwise and the reaction mixture wasstirred at RT overnight. Thereafter, at 0° C., another 9.86 ml (19.73mmol) of a 2M solution of ethylamine in THF were added and the reactionwas stirred at RT for a further 5 h. Subsequently, at 0° C., a further4.93 ml (9.86 mmol) of a 2M solution of ethylamine in THF were added andstirring was continued overnight. For workup, the reaction mixture wasadmixed with saturated sodium hydrogencarbonate solution and extractedthree times with ethyl acetate. The combined organic phases were driedover magnesium sulphate, filtered and concentrated. The resultingresidue was subjected to extractive stirring in MTBE and theprecipitated solid was filtered off with suction. The filtrate wasconcentrated to obtain an overall yield of 2.29 g (100% of theory) ofthe title compound.

LC-MS (Method 1): R_(t)=0.97 min; MS (ESIpos): m/z=212 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 3.49-3.58 (m, 2H), 7.23(d, 1H), 8.26 (dd, 1H), 8.81-8.89 (m, 2H).

Example 43A N¹-ethyl-4-nitrobenzene-1,2-diamine

1.20 g (5.68 mmol) of N-ethyl-2,4-dinitroaniline from Example 42A wereinitially charged in 3 ml of acetonitrile under argon and 64 mg (0.06mmol) of palladium (10% on activated carbon) and 3.40 ml (24.38 mmol) oftriethylamine were added. The reaction mixture was cooled to −15° C.,and a solution of 1.03 ml (27.44 mmol) of formic acid in 3 ml ofacetonitrile was added. The reaction mixture was stirred at 40° C. for 1h and at 60° C. for 2 h. For workup, the reaction mixture at RT wasfiltered through kieselguhr and washed with ethyl acetate/methanol(1:1), and the filtrate was concentrated. The residue was admixed withwater, and the precipitated solid was filtered off with suction, washedwith water and dried at 50° C. under reduced pressure. This gave 546 mg(47% of theory) of the title compound.

LC-MS (Method 1): R_(t)=0.79 min; MS (ESIpos): m/z=182 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 3.18-3.26 (m, 2H),5.09-5.20 (m, 2H), 5.87 (t, 1H), 6.46 (d, 1H), 7.39 (d, 2H), 7.52 (dd,1H).

Example 44A 1-ethyl-5-nitro-1H-benzimidazole

540 mg (2.98 mmol) of N¹-ethyl-4-nitrobenzene-1,2-diamine from Example43A were initially charged in 19 ml of (diethoxymethoxy)ethane, then0.32 ml (3.89 mmol) of conc. hydrochloric acid were added dropwise andthe reaction mixture was stirred at RT for 2 h. Subsequently, themixture was concentrated under reduced pressure, and the residue wassubjected to extractive stirring in MTBE, filtered off, washed with MTBEand dried. This gave 486 mg (54% of theory) of the title compound.

LC-MS (Method 1): R_(t)=0.65 min; MS (ESIpos): m/z=192 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.46 (t, 3H), 4.42 (q, 2H), 7.97 (d,1H), 8.26 (d, 1H), 8.60 (d, 1H), 8.83-8.90 (m, 1H).

Example 45A 1-ethyl-1H-benzimidazol-5-amine

The preparation and purification of the target compound were analogousto Example 33A, and the reaction took place overnight. Proceeding from485 mg (2.53 mmol) of 1-ethyl-5-nitro-1H-benzimidazole from Example 44A,417 mg (101% of theory) of the title compound were obtained.

LC-MS (Method 2): R_(t)=0.23 min; MS (ESIpos): m/z=162 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.47 (t, 3H), 4.36 (q, 2H), 6.85-6.96(m, 2H), 7.64 (d, 1H), 9.16 (s, 1H).

Example 46A ethyl1-(1-ethyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

659 mg (2.54 mmol) of ethyl3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate and 410 mg (2.54 mmol) of1-ethyl-1H-benzimidazol-5-amine from Example 45A were initially chargedin 19 ml of ethanol and the mixture was stirred at reflux for 2 h.Thereafter, at RT, 285 mg (2.54 mmol) of potassium tert-butoxide wereadded and the reaction mixture was heated to reflux for 3 h. For workup,the reaction mixture was admixed with water and the mixture wasconcentrated under reduced pressure. The residue was stirred withdichloromethane/methanol and filtered, and the filtrate wasconcentrated. The residue thus obtained was stirred in MTBE/ethylacetate, and the solid was filtered off, washed with ethyl acetate andthen dried at 50° C. under reduced pressure. This gave 491 mg (59% oftheory) of the title compound.

LC-MS (Method 3): R_(t)=0.60 min; MS (ESIpos): m/z=329 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.17-1.23 (m, 3H), 1.42 (t, 3H),4.08-4.16 (m, 2H), 4.28-4.36 (m, 2H), 7.26 (d, 1H), 7.63-7.71 (m, 2H),8.15 (s, 1H), 8.35 (s, 1H).

Example 47A N-isopropyl-2,4-dinitroaniline

1.00 g (4.93 mmol) of 1-chloro-2,4-dinitrobenzene were initially chargedin 10 ml of THF, then 0.84 ml (9.87 mmol) of isopropylamine was addeddropwise and the reaction mixture was stirred at RT for 16 h. Forworkup, the mixture was admixed with saturated sodium hydrogencarbonatesolution and washed three times with ethyl acetate, and the combinedorganic phases were dried over magnesium sulphate, filtered andconcentrated. This gave 1.13 g (99% of theory) of the title compound.

LC-MS (Method 3): R_(t)=1.30 min; MS (ESIpos): m/z=226 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.31 (d, 6H), 4.02-4.15 (m, 1H), 7.27(d, 1H), 8.27 (dd, 1H), 8.42 (d, 1H), 8.86 (d, 1H).

Example 48A N¹-isopropyl-4-nitrobenzene-1,2-diamine

The preparation and purification of the target compound were analogousto Example 43A, with a reaction time of 7 h. Proceeding from 1.13 g(5.01 mmol) of N-isopropyl-2,4-dinitroaniline from Example 47A, 708 mg(72% of theory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.88 min; MS (ESIpos): m/z=196 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.21 (d, 6H), 3.69-3.81 (m, 1H),5.11-5.24 (m, 2H), 5.62 (d, 1H), 6.49 (d, 1H), 7.39 (d, 1H), 7.51 (dd,1H).

Example 49A 1-isopropyl-5-nitro-1H-benzimidazole

The preparation of the target compound was analogous to Example 39A,using 700 mg (3.58 mmol) of N¹-isopropyl-4-nitrobenzene-1,2-diamine fromExample 48A and 23 ml (137.49 mmol) of (diethoxymethoxy)ethane. Forworkup, the mixture was concentrated, and the residue was stirred withMTBE, filtered off and dried under high vacuum. This gave 760 mg of thetitle compound. The crude product was converted without furtherpurification.

LC-MS (Method 3): R_(t)=0.98 min; MS (ESIpos): m/z=206 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.58 (d, 6H), 4.88-4.99 (m, 1H), 8.01(d, 1H), 8.24 (dd, 1H), 8.60 (d, 1H), 8.94-9.01 (m, 1H).

Example 50A 1-isopropyl-1H-benzimidazol-5-amine

The preparation and purification of the target compound were analogousto Example 33A, with a reaction time of 16 h. Proceeding from 750 mg(3.65 mmol) of 1-isopropyl-5-nitro-1H-benzimidazole from Example 49A,612 mg (95% of theory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.23 min; MS (ESIpos): m/z=176 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.56 (d, 6H), 3.34 (s, concealed bywater signal), 4.77-4.90 (m 1H), 6.87-6.95 (m, 2H), 7.67 (d, 1H), 9.22(s, 1H).

Example 51A ethyl1-(1-isopropyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the target compound were analogousto Example 27A. Proceeding from 612 mg (3.49 mmol) of1-isopropyl-1H-benzimidazol-5-amine from Example 50A and 905 mg (3.49mmol) of ethyl 3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate, 684 mg(57% of theory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.56 min; MS (ESIpos): m/z=343 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.21 (t, 3H), 1.56 (d, 6H), 4.15 (q,2H), 4.81 (spt, 1H), 7.32 (d, 1H), 7.71-7.79 (m, 2H), 8.26 (s, 1H), 8.47(s, 1H), 11.66 (br.s, 1H).

Example 52A N-{4-[(cyclopropylmethyl)amino]-3-nitrophenyl}acetamide

The preparation and purification of the target compound were analogousto Example 37A. Proceeding from 1.00 g (5.04 mmol) ofN-(4-fluoro-3-nitrophenyl)acetamide and 1.04 ml (10.09 mmol) ofcyclopropylmethylamine, 1.34 g of the title compound were obtained. Thecrude product was converted without further purification.

LC-MS (Method 3): R_(t)=1.10 min; MS (ESIpos): m/z=250 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=0.27-0.33 (m, 2H), 0.49-0.55 (m, 2H),1.10-1.22 (m, 1H), 2.02 (s, 3H), 3.21 (t, 2H), 7.07 (d, 1H), 7.65 (dd,1H), 8.09 (t, 1H), 8.46 (d, 1H), 9.96 (s, 1H).

Example 53A N-{3-amino-4-[(cyclopropylmethyl)amino]phenyl}acetamide

The preparation and purification of the target compound were analogousto Example 38A. Proceeding from 1.10 g (4.41 mmol) ofN-{4-[(cyclopropylmethyl)amino]-3-nitrophenyl}acetamide from Example52A, 952 mg (98% of theory) of the title compound were obtained.

LC-MS (Method 2): R_(t)=0.92 min; MS (ESIpos): m/z=220 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=0.17-0.23 (m, 2H), 0.42-0.52 (m, 2H),1.01-1.13 (m, 1H), 1.93 (s, 3H), 2.83 (t, 2H), 4.22 (t, 1H), 4.50-4.65(m, 2H), 6.31 (d, 1H), 6.64 (dd, 1H), 6.84 (d, 1H), 9.36 (s, 1H).

Example 54A N-[1-(cyclopropylmethyl)-1H-benzimidazol-5-yl]acetamide

The preparation and purification of the target compound were analogousto Example 39A. Proceeding from 951 mg (4.33 mmol) ofN-{3-amino-4-[(cyclopropylmethyl)amino]phenyl}acetamide from Example 53Aand 28 ml (166.29 mmol) of (diethoxymethoxy)ethane, 929 mg (84% oftheory) of the title compound were obtained.

LC-MS (Method 3): R_(t)=0.39 min; MS (ESIpos): m/z=230 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=0.47-0.53 (m, 2H), 0.58-0.64 (m, 2H),1.32-1.43 (m, 1H), 2.10 (s, 3H), 4.25 (d, 2H), 7.55 (dd, 1H), 7.87 (d,1H), 8.30 (d, 1H), 9.22 (s, 1H), 10.34 (s, 1H).

Example 55A 1-(cyclopropylmethyl)-1H-benzimidazol-5-amine

The preparation and purification of the target compound were analogousto Example 40A. Proceeding from 828 mg (3.61 mmol) ofN-[1-(cyclopropylmethyl)-1H-benzimidazol-5-yl]acetamide from Example54A, 482 mg (70% of theory) of the title compound were obtained.

LC-MS (Method 2): R_(t)=0.87 min; MS (ESIpos): m/z=188 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=0.34-0.40 (m, 2H), 0.48-0.55 (m, 2H),1.19-1.30 (m, 1H), 3.96 (d, 2H), 4.71 (br.s, 2H), 6.59 (dd, 1H), 6.77(d, 1H), 7.27 (d, 1H), 7.97 (s, 1H).

Example 56A ethyl1-[1-(cyclopropylmethyl)-1H-benzimidazol-5-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation of the target compound was analogous to Example 31A,with a reaction time of 5 h using 547 mg (2.92 mmol) of1-(cyclopropylmethyl)-1H-benzimidazol-5-amine from Example 55A and 757mg (2.92 mmol) of ethyl 3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate.For workup, the reaction mixture was concentrated, the residue wassubjected to extractive stirring in ethyl acetate/methanol, and thesolid was filtered off with suction and dried under high vacuum. Thisgave 1.02 g (98% of theory) of the title compound.

LC-MS (Method 1): R_(t)=0.61 min; MS (ESIpos): m/z=355 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=0.41-0.46 (m, 2H), 0.51-0.58 (m, 2H),1.18 (t, 3H), 1.25-1.37 (m, 1H), 4.06 (q, 2H), 4.15 (d, 2H), 7.18 (dd,1H), 7.53 (d, 1H), 7.67 (d, 1H), 7.97 (s, 1H), 8.33 (s, 1H).

Example 57A 1,3,3-trimethyl-5-nitro-1,3-dihydro-2H-indol-2-one

2.44 g (13.96 mmol) of 1,3,3-trimethyl-1,3-dihydro-2H-indol-2-one [forpreparation see: Journal of Organic Chemistry, 2000, vol. 65, 24, p.8317-8325] were initially charged in 12 ml of acetic acid, then 0.96 ml(13.96 mmol) of nitric acid (65%) was added dropwise at RT and thereaction mixture was stirred at RT for 2 weeks. The reaction mixture wasadded to ice-water, and the precipitated solid was filtered off withsuction, washed with water and dried at 50° C. under reduced pressure.This gave 2.32 g (72% of theory) of the title compound.

LC-MS (Method 5): R_(t)=0.89 min; MS (ESIpos): m/z=221 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.35 (s, 6H), 3.22 (s, 3H), 7.25 (d,1H), 8.26 (dd, 1H), 8.33 (d, 1H).

Example 58A 5-amino-1,3,3-trimethyl-1,3-dihydro-2H-indol-2-one

The preparation and purification of the target compound were analogousto Example 33A, with a reaction time of 2 days. Proceeding from 2.32 g(10.56 mmol) of 1,3,3-trimethyl-5-nitro-1,3-dihydro-2H-indol-2-one fromExample 57A, 1.95 g (93% of theory) of the title compound were obtained.

LC-MS (Method 2): R_(t)=0.76 min; MS (ESIpos): m/z=191 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.20 (s, 6H), 3.04 (s, 3H), 4.70-4.80(m, 2H), 6.46 (dd, 1H), 6.58 (d, 1H), 6.67 (d, 1H).

Example 59A ethyl2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the target compound were analogousto Example 31A. Proceeding from 1.95 g (10.26 mmol) of5-amino-1,3,3-trimethyl-1,3-dihydro-2H-indol-2-one from Example 58A and2.66 g (10.26 mmol) ofethyl-3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate, 2.84 g (77% oftheory) of the title compound were obtained.

LC-MS (Method 2): R_(t)=1.62 min; MS (ESIpos): m/z=358 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 1.29 (s, 6H), 3.17 (s,3H), 4.17 (q, 2H), 7.13 (d, 1H), 7.40 (dd, 1H), 7.51 (d, 1H), 8.25 (s,1H), 11.65-11.71 (m, 1H).

Example 60A 1′-methylspiro[cyclopropane-1,3′-indole]-2′(1′H)-one

5.43 g (135.89 mmol) of sodium hydride (60% in mineral oil) wereinitially charged in 40 ml of DMF, then, at 0° C., a solution of 5.00 g(33.97 mmol) of 1-methyl-1,3-dihydro-2H-indol-2-one in 40 ml of DMF wereadded dropwise and the reaction mixture was stirred at RT for 30 min.Subsequently, 8.81 ml (101.91 mmol) of dibromoethane were added dropwiseand the mixture was stirred at RT for 1 h. For workup, the reactionmixture was admixed with water and washed three times with ethylacetate, and the combined organic phases were dried over magnesiumsulphate, filtered and concentrated. This gave 3.78 g (64% of theory) ofthe title compound.

LC-MS (Method 1): R_(t)=0.76 min; MS (ESIpos): m/z=174 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.48-1.53 (m, 2H), 1.57-1.61 (m, 2H),3.21 (s, 3H), 6.97-7.03 (m, 2H), 7.06 (d, 1H), 7.23-7.28 (m, 1H).

Example 61A1′-methyl-5′-nitrospiro[cyclopropane-1,3′-indole]-2′(1′H)-one

3.77 g (21.79 mmol) of1′-methylspiro[cyclopropane-1,3′-indole]-2′(1′H)-one from Example 60Awere initially charged in 40 ml of glacial acetic acid, then 0.90 ml(21.79 mmol) of conc. nitric acid were added dropwise, and the mixturewas stirred at RT for 2 h. Thereafter, a further 0.45 ml (10.89 mmol) ofconc. nitric acid was added dropwise and the mixture was stirred at RTfor a further 1.5 h. For workup, the mixture was added to ice-water, andthe precipitated solid was filtered off with suction, washed with waterand dried at 30° C. under reduced pressure. This gave 4.01 g (84% oftheory) of the title compound.

GC-MS (Method 6): R_(t)=7.21 min; MS (ESIpos): m/z=219 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.54-1.72 (m, 2H), 1.80-1.99 (m, 2H),3.3 (s, partly concealed by water signal), 7.17-7.38 (m, 1H), 7.91-8.09(m, 1H), 8.14-8.31 (m, 1H).

Example 62A5′-amino-1′-methylspiro[cyclopropane-1,3′-indole]-2′(1′H)-one

1.00 g (4.58 mmol) of1′-methyl-5′-nitrospiro[cyclopropane-1,3′-indole]-2′(1′H)-one fromExample 61A were initially charged in 11 ml of ethyl acetate, 4.13 g(18.33 mmol) of tin(II) chloride dihydrate were added and the mixturewas heated to reflux for 2.5 h. The reaction mixture cooled to RT wasdiluted with ethyl acetate and extracted twice with 1 N hydrochloricacid. The aqueous phase was set to pH 10 with 1N sodium hydroxidesolution and extracted four times with dichloromethane. The combinedorganic phases were washed with saturated sodium chloride solution,dried over magnesium sulphate, filtered and concentrated. This gave 375mg (42% of theory) of the title compound.

LC-MS (Method 2): R_(t)=0.73 min; MS (ESIpos): m/z=189 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.38-1.46 (m, 4H), 3.11 (s, 3H),4.65-4.76 (m, 2H), 6.24 (d, 1H), 6.46 (dd, 1H), 6.73 (d, 1H).

Example 63A ethyl1-(1′-methyl-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-5′-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

510 mg (1.97 mmol) of ethyl3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate and 370 mg (1.97 mmol) of5′-amino-1-methylspiro[cyclopropane-1,3′-indole]-2′(1′H)-one fromExample 62A were heated to reflux in 10 ml of ethanol for 45 min.Thereafter, at RT, 221 mg (1.97 mmol) of potassium tert-butoxide wereadded and the mixture was stirred at RT for 1.5 h and to reflux for 1 h.For workup, the reaction mixture was admixed with water and acidifiedwith 1N hydrochloric acid. The solid formed was filtered off, washedwith water, and then dried under reduced pressure at 30° C. This gave557 mg (78% of theory) of the title compound.

LC-MS (Method 1): R_(t)=0.69 min; MS (ESIpos): m/z=356 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 1.54-1.59 (m, 2H),1.62-1.68 (m, 2H), 3.25 (s, 3H), 4.17 (q, 2H), 7.15-7.20 (m, 2H),7.35-7.41 (m, 1H), 8.25 (s, 1H), 11.68 (s, 1H).

Example 64A ethyl2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate

388 mg (1.49 mmol) of ethyl3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate and 285 mg (1.49 mmol) of6-amino-1,3,3-trimethyl-1,3-dihydro-2H-indol-2-one [for preparation see:Journal of Medicinal Chemistry, 1989, Vol. 32, (7), 1481-1491] wereinitially charged in 10 ml of ethanol and the mixture was heated toreflux for 2 h. Thereafter, at RT, 167 mg (1.49 mmol) of potassiumtert-butoxide were added and the mixture was stirred at RT for 1 h andat reflux for 15 min. For workup, the reaction mixture was admixed withwater, acidified with 1N hydrochloric acid and extracted twice withethyl acetate. The combined organic phases were dried over magnesiumsulphate, filtered and concentrated. The residue was subjected toextractive stirring in MTBE/ethyl acetate, filtered off, washed withethyl acetate and then dried at 50° C. under reduced pressure. The solidwhich precipitated in the filtrate was filtered off with suction anddried under reduced pressure. This gave a total of 388 mg (68% oftheory) of the title compound.

LC-MS (Method 1): R_(t)=0.75 min; MS (ESIpos): m/z=358 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 1.30 (s, 6H), 3.14 (s,3H), 4.17 (q, 2H), 7.16 (d, 1H), 7.23 (s, 1H), 7.48 (d, 1H), 8.30 (s,1H), 11.73 (s, 3H).

Example 65A ethyl1-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

570 mg (2.20 mmol) of ethyl3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate and 388 mg (2.20 mmol) of6-amino-3,3-dimethyl-1,3-dihydro-2H-indol-2-one [for preparation see: US2006/258689, page 35] were initially charged in 14 ml of ethanol andheated to reflux for 2 h. Subsequently, at RT, 247 mg (2.20 mmol) ofpotassium tert-butoxide were added and the mixture was stirred at RT for1 h and at 60° C. for 1 h. For workup, the reaction mixture was admixedwith water, acidified with 1N hydrochloric acid and extracted twice withethyl acetate. The combined organic phases were dried over magnesiumsulphate, filtered and concentrated. The residue was subjected toextractive stirring in MTBE/ethyl acetate, and the solid formed wasfiltered off, washed with ethyl acetate and then dried at 50° C. underreduced pressure. This gave 630 mg (79% of theory) of the titlecompound.

LC-MS (Method 1): R_(t)=0.65 min; MS (ESIpos): m/z=344 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 1.28 (s, 6H), 4.16 (q,2H), 6.96-7.01 (m, 1H), 7.04-7.09 (m, 1H), 7.42 (d, 1H), 8.27 (s, 1H),10.58 (s, 1H), 11.65 (s, 1H).

Example 66A ethyl1-(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the target compound were analogousto Example 31A. Proceeding from 0.81 g (3.96 mmol) of1-(6-amino-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)ethanone [synthesisdescribed in: WO 2006/12374 A1, 2006] and 1.06 g (3.96 mmol) of ethyl3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate, 626 mg (40% of theory)of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.84 min; MS (ESIpos): m/z=372 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 1.34 (s, 6H), 2.18 (s,3H), 3.93 (s, 2H), 4.16 (q, 2H), 7.13 (dd, 1H), 7.38 (d, 1H), 8.05 (d,1H), 8.23 (s, 1H), 11.64 (br.s, 1H).

Example 67A 5-bromo-1,3,3-trimethyl-1,3-dihydro-2H-indol-2-one

Under argon, 2.64 g (66 mmol) of sodium hydride (60% in mineral oil)were suspended in 25 ml of THF and cooled to 0° C. A solution of 4.00 g(18.86 mmol) of 5-bromo-1,3-dihydro-2H-indol-2-one in 25 ml of DMF wasadded dropwise and the mixture was stirred at 0° C. for 30 min.Subsequently, 4.11 ml (66 mmol) of methyl iodide were slowly addeddropwise thereto, then the reaction mixture was warmed to RT andstirring continued at this temperature overnight. For workup, themixture was poured onto 200 ml of 1M hydrochloric acid and extractedthree times with ethyl acetate. The combined organic phases were washedwith water, then a saturated sodium chloride solution, dried over sodiumsulphate and concentrated on a rotary evaporator. The residue wasdissolved in 200 ml of acetonitrile and the mineral oil was extractedwith n-pentane. The acetonitrile phase removed was concentrated on arotary evaporator and the remaining brownish solid was dried under HV.This gave 4.45 g (84% of theory) of the title compound in 91% purity.

LC-MS (Method 3): R_(t)=1.18 min; m/z=254, 256 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.27 (s, 6H), 3.12 (s, 3H), 6.99 (d,1H), 7.45 (dd, 1H), 7.60 (d, 1H).

Example 68A1,3,3-trimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-indol-2-one

A solution of 3.45 g (approx. 12.35 mmol) of the compound from Example67A, 4.71 g (18.5 mmol) of4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane(bispinacolatodiboron) and 2.18 g (22.2 mmol) of potassium acetate in 60ml of dioxane was degassed and put under an argon atmosphere. 1.0 g(1.23 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)dichloride dichloromethane complex was added and the mixture was heatedto reflux overnight. After cooling to RT, the reaction mixture wasfiltered through Celite, Celite was washed with ethyl acetate and theoverall filtrate was concentrated on a rotary evaporator. The residuewas adsorbed on diatomaceous earth in dichloromethane and applied to aBiotage silica gel cartridge. The cartridge was eluted withcyclohexane/ethyl acetate. The product-containing fractions wereconcentrated on a rotary evaporator. The residue was stirred with 20 mlof diethyl ether. The solid was filtered off, washed with a littlediethyl ether and dried under HV. This gave 1.82 g of the titlecompound. By concentrating the mother liquor, stirring the residue inpentane and filtering off the solid, an additional 1.13 g of productwere obtainable. Overall yield: 79% of theory.

LC-MS (Method 1): R_(t)=1.09 min; m/z=302 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.27 (s, 6H), 1.29 (s, 12H), 3.14 (s,3H), 7.03 (d, 1H), 7.58 (br.s, 1H), 7.62 (br d, 1H).

Example 69A ethyl1-[3-hydroxy-1-methyl-2-oxo-3-(trifluoromethyl)-2,3-dihydro-1H-indol-5-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate)

1.00 g (4.06 mmol) of5-amino-3-hydroxy-1-methyl-3-(trifluoromethyl)-1,3-dihydro-2H-indol-2-onefrom Example 20A and 1.05 g (4.06 mmol) of ethyl3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate were heated to reflux in100 ml of ethanol for 1 h. After cooling to RT, 0.46 mg (4.06 mmol) ofpotassium tert-butoxide was added and the reaction mixture was stirredfurther at RT overnight and to reflux for 1 h. For workup, the reactionmixture was acidified with 1M hydrochloric acid, diluted with water andpartly concentrated. The solid formed was filtered off, washed withwater, and dried under reduced pressure at 40° C. overnight. This gave1.47 g (88% of theory) of the target compound.

LC-MS (Method 1): R_(t)=0.72 min; MS (ESIpos): m/z=414 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.24 (t, 3H), 3.21 (s, 3H), 4.18 (q,2H), 7.27 (d, 1H), 7.60-7.68 (m, 2H), 7.90 (s, 1H), 8.23 (s, 1H), 11.68(s, 1H).

Example 70A 3-hydroxy-1,3-dimethyl-5-nitro-1,3-dihydro-2H-indol-2-one(racemate)

Under argon, 8.70 g (42.20 mmol) of 1-methyl-5-nitro-1H-indole-2,3-dione[for preparation see: Bioorganic & Medicinal Chemistry, 2006, 14(18), p.6434-6443] were initially charged in 200 ml, then, at 0° C., 33 ml(46.42 mmol) of a 1.4M solution of magnesium bromide in toluene/THF wereadded dropwise within 10 min and the reaction mixture was stirred at RTfor 16 h. For workup, the reaction mixture was admixed with cold waterand extracted twice with dichloromethane. The combined organic phaseswere dried over magnesium sulphate, filtered and concentrated. Theresidue was separated by means of preparative HPLC (Method 7). This gave1.41 g (12% of theory) of the title compound.

LC-MS (Method 5): R_(t)=0.63 min; MS (ESIpos): m/z=223 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.46 (s, 3H), 3.19 (s, 3H), 3.22 (s,1H), 7.24 (d, 1H), 8.19 (d, 1H), 8.30 (dd, 1H).

Example 71A 5-amino-3-hydroxy-1,3-dimethyl-1,3-dihydro-2H-indol-2-one(racemate)

The preparation and purification of the target compound were analogousto Example 33A, with a reaction time of 4 h. Proceeding from 1.40 g(6.30 mmol) of 3-hydroxy-1,3-dimethyl-5-nitro-1,3-dihydro-2H-indol-2-onefrom Example 70A, after additional purification by means of preparativeHPLC (Method 24), 1.15 g (95% of theory) of the title compound wereobtained.

LC-MS (Method 2): R_(t)=0.48 min; MS (ESIpos): m/z=193 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.39 (s, 3H), 3.11 (s, 3H), 7.08 (d,1H), 7.25-7.32 (m, 2H).

Example 72A ethyl1-(3-hydroxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate)

674 mg (2.60 mmol) of ethyl3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate and 500 mg (2.60 mmol) of5-amino-3-hydroxy-1,3-dimethyl-1,3-dihydro-2H-indol-2-one from Example71A were initially charged in 15 ml of ethanol and the mixture washeated to reflux for 1.5 h. Thereafter, at RT, 292 mg (2.60 mmol) ofpotassium tert-butoxide were added and the reaction mixture was heatedto reflux for 10 h. For workup, the reaction mixture at RT was acidifiedwith 1N hydrochloric acid and extracted twice with ethyl acetate. Thecombined organic phases were washed with saturated sodium chloridesolution, dried over magnesium sulphate, filtered and concentrated. Theresidue was stirred in MTBE/ethyl acetate, and the solid formed wasfiltered off and then dried at 30° C. under reduced pressure. The solidwhich precipitated in the filtrate was filtered off, washed with waterand dried under reduced pressure. This gave a total of 218 mg (22% oftheory) of the title compound.

LC-MS (Method 5): R_(t)=0.53 min; MS (ESIpos): m/z=360 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 1.41 (s, 3H), 3.14 (s,3H), 4.18 (q, 2H), 6.10 (s, 1H), 7.11 (d, 1H), 7.43 (d, 1H), 7.52 (s,1H), 8.20 (s, 1H), 11.67 (s, 1H).

Example 73A ethyl1-[3-fluoro-1-methyl-2-oxo-3-(trifluoromethyl)-2,3-dihydro-1H-indol-5-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate)

Under argon, 200 mg (0.48 mmol) of ethyl1-[3-hydroxy-1-methyl-2-oxo-3-(trifluoromethyl)-2,3-dihydro-1H-indol-5-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 69A were initially charged at −78° C. in 4.74 ml ofdichloromethane. Subsequently, 128 μl (0.97 mmol) of diethylaminosulphurtrifluoride were added dropwise, and the mixture was brought to RT andstirred further overnight. Thereafter, diethylaminosulphur trifluoride(0.5 eq.) was again added at −78° C. and the mixture was stirred at RTfor 1 h. For workup, the mixture was diluted with dichloromethane,washed once each with saturated sodium hydrogencarbonate solution andsaturated sodium chloride solution, dried over magnesium sulphate,filtered and concentrated. This gave 191 mg (91% of theory) of the titlecompound.

LC-MS (Method 5): R_(t)=0.83 min; MS (ESIpos): m/z=416 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 3.26 (s, 3H), 4.18 (q,2H), 7.40 (d, 1H), 7.77-7.83 (m, 1H), 7.91 (s, 1H), 8.34 (s, 1H), 11.72(s, 1H).

Example 74A ethyl1-(1-methyl-1H-benzotriazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

717 mg (2.77 mmol) of ethyl3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate and 410 mg (2.77 mmol) of1-methyl-1H-benzotriazol-5-amine [for preparation see: WO 2005/092899,Ex. 142; Preparation 265] were heated to reflux in 21 ml of ethanol for2 h. Thereafter, at RT, 311 mg (2.77 mmol) of potassium tert-butoxidewere added and the reaction mixture was heated to reflux for a further 3h. For workup, the reaction mixture was admixed with water and acidifiedwith 1N hydrochloric acid. The solid formed was filtered off, washedwith ethyl acetate and dried under reduced pressure at 50° C. This gave659 mg (76% of theory) of the title compound.

LC-MS (Method 1): R_(t)=0.59 min; MS (ESIpos): m/z=316 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 4.18 (q, 2H), 4.36 (s,3H), 7.68 (dd, 1H), 7.97 (d, 1H), 8.25-8.29 (m, 1H), 8.40 (s, 1H), 11.75(s, 1H).

Example 75A ethyl1-(1-methyl-1H-indazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

1.76 g (6.79 mmol) of ethyl3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate and 1.00 g (6.79 mmol) of1-methyl-1H-indazol-5-amine in 51 ml of ethanol were heated to refluxfor 2 h. Thereafter, at RT, 762 mg (6.79 mmol) of potassiumtert-butoxide were added and the reaction mixture was heated to refluxfor a further 3 h. For workup, the reaction mixture was admixed withwater and acidified with 1N hydrochloric acid. The solid formed wasfiltered off, washed with ethyl acetate/MTBE (1:1) and dried underreduced pressure at 50° C. This gave 1.97 g (92% of theory) of the titlecompound.

LC-MS (Method 1): R_(t)=0.62 min; MS (ESIpos): m/z=315 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 4.09 (s, 3H), 4.17 (q,2H), 7.45-7.52 (m, 1H), 7.75 (d, 1H), 7.91 (s, 1H), 8.15 (s, 1H), 8.32(s, 1H), 11.68 (s, 1H).

Example 76A ethyl1-(1-methyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

1.76 g (6.79 mmol) of ethyl3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate and 1.00 g (6.79 mmol) of1-methyl-1H-benzimidazol-5-amine [for preparation see: US 2008/0090856,Ex. B23] in 51 ml of ethanol were heated to reflux for 2 h. Thereafter,at RT, 0.76 g (6.79 mmol) of potassium tert-butoxide were added and thereaction mixture was heated to reflux for a further 3 h. For workup, thereaction mixture was admixed with water and acidified with 1Nhydrochloric acid. The aqueous phase was concentrated,dichloromethane/methanol (1:1) was added and the solid formed wasfiltered off. The filtrate was concentrated, MTBE/ethyl acetate (1:1)was added, and the solid formed was filtered off, washed with ethylacetate and then dried at 50° C. under reduced pressure. This gave 1.55g (73% of theory) of the title compound.

LC-MS (Method 2): R_(t)=1.00 min; MS (ESIpos): m/z=315 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 4.03 (s, 3H), 4.18 (q,2H), 7.62-7.68 (m, 1H), 7.94-8.00 (m, 1H), 8.00-8.03 (m, 1H), 8.35 (s,1H), 9.24 (br.s, 1H), 11.73 (s, 1H).

Example 77A 1-methyl-5-nitro-2-(trichloromethyl)-1H-benzimidazole

To a suspension, cooled to 0° C., of 1.50 g (8.97 mmol) ofN¹-methyl-4-nitrobenzene-1,2-diamine in 40.0 ml of glacial acetic acidwere added dropwise 1.22 ml (9.87 mmol) of methyl2,2,2-trichloroacetimidate and the mixture was stirred at RT for 3 h.For workup, the mixture was added to water, and the solid was filteredoff and washed with water. The solid was dried at 50° C. under highvacuum. This gave 2.50 g (93% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.06 min; MS (ESIpos): m/z=296 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=4.20 (s, 3H), 8.00 (d, 1H), 8.35 (dd,1H), 8.75 (d, 1H).

Example 78A ethyl 1-methyl-5-nitro-1H-benzimidazole-2-carboxylate

2.50 g (8.48 mmol) of1-methyl-5-nitro-2-(trichloromethyl)-1H-benzimidazole from Example 77Awere initially charged in 24.0 ml of ethanol, then 4.75 g (27.98 mmol)of silver(I) nitrate were added and the mixture was heated to refluxovernight. For workup, the mixture was concentrated and the residue wasadmixed with 1M hydrochloric acid and ethyl acetate. Thereafter, themixture was filtered through Celite and washed with ethyl acetate. Theorganic phase was dried over magnesium sulphate, filtered andconcentrated. The resulting residue was stirred with MTBE, and the solidformed was filtered off and washed with MTBE. The solid was dried underhigh vacuum. This gave 0.32 g (15% of theory) of the title compound.

LC-MS (Method 5): R_(t)=0.86 min; MS (ESIpos): m/z=250 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.39 (t, 3H), 4.15 (s, 3H), 4.44 (q,2H), 7.99 (d, 1H), 8.28-8.35 (m, 1H), 8.69-8.74 (m, 1H).

Example 79A 1-methyl-5-nitro-1H-benzimidazole-2-carboxamide

745 mg (2.99 mmol) of ethyl1-methyl-5-nitro-1H-benzimidazole-2-carboxylate from Example 78A wereinitially charged in 10.0 ml of THF, then 27.4 ml (54.90 mmol) of 25%aqueous ammonia solution were added and the mixture was stirred at RTfor 2.5 h. For workup, the reaction mixture was admixed with water, andthe solid formed was filtered off, washed with water and dried underhigh vacuum at 50° C. This gave 512 mg (88% purity, 68% of theory) ofthe title compound.

LC-MS (Method 5): R_(t)=0.64 min; MS (ESIpos): m/z=221 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=4.18 (s, 3H), 7.94 (d, 1H), 8.04(br.s, 1H), 8.28 (dd, 1H), 8.46 (br.s, 1H), 8.60 (d, 1H).

Example 80A 5-amino-1-methyl-1H-benzimidazole-2-carboxamide

512 mg (2.33 mmol) of the nitro compound from Example 79A were initiallycharged in 16 ml of ethanol, then 74 mg (0.07 mmol) of palladium (10% onactivated carbon) were added and the mixture was hydrogenated atstandard hydrogen pressure overnight. Subsequently, the reaction mixturewas filtered through kieselguhr, the residue was washed with ethanol andthe filtrate was concentrated. This gave 440 mg (90% purity, 90% oftheory) of the target compound.

LC-MS (Method 5): R_(t)=0.19 min; MS (ESIpos): m/z=191 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=4.02 (s, 3H), 4.88-4.96 (m, 2H),6.73-6.77 (m, 1H), 6.77-6.81 (m, 1H), 7.31 (d, 1H), 7.64 (br.s, 1H),8.06 (br.s, 1H).

Example 81A ethyl1-(2-carbamoyl-1-methyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the target compound were analogousto Example 31A. Proceeding from 440 mg (2.31 mmol) of5-amino-1-methyl-1H-benzimidazole-2-carboxamide from Example 80A and 600mg (2.31 mmol) of ethyl 3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate,158 mg (87% purity, 17% of theory) of the title compound were obtained.The crude product was converted without further purification.

LC-MS (Method 1): R_(t)=0.55 min; MS (ESIpos): m/z=358 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 4.13-4.21 (m, 5H),7.46-7.53 (m, 1H), 7.80 (d, 1H), 7.89-7.93 (m, 2H), 8.31-8.37 (m, 2H),11.69 (s, 1H).

Example 82A ethyl1-(1-methyl-1H-benzimidazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the target compound were analogousto Example 31A. Proceeding from 1.00 g (6.79 mmol) of1-methyl-1H-benzimidazol-6-amine and 1.76 g (6.79 mmol) of ethyl3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate, 1.03 g (48% of theory)of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.36 min; MS (ESIpos): m/z=315 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 4.01 (s, 3H), 4.19 (q,2H), 7.61-7.67 (m, 1H), 7.90-7.96 (m, 1H), 8.15 (s, 1H), 8.37 (s, 1H),9.29-9.37 (m, 1H), 11.80 (s, 1H).

Example 83A 1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide

1.00 g (9.25 mmol) of 1,2-phenylenediamine and 2.67 g (27.74 mmol) ofsulphamide were initially charged in 14 ml of pyridine and the mixturewas stirred at 130° C. overnight. For workup, the reaction mixture wasconcentrated under reduced pressure and the residue was separated bymeans of flash silica gel chromatography (cyclohexane/ethyl acetategradient 7:1, 5:1). This gave 659 mg (42% of theory) of the titlecompound.

LC-MS (Method 5): R_(t)=0.51 min; MS (ESIpos): m/z=171 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=6.76-6.83 (m, 2H), 6.85-6.91 (m, 2H),10.95 (br.s, 2H).

Example 84A 1,3-dimethyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide

Under argon, 1.54 g (38.45 mmol) of sodium hydride (60% in mineral oil)in 41 ml of DMF were initially charged, then, at 0° C., a solution of2.62 g (15.38 mmol) of 1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxidefrom Example 83A in 5 ml of DMF was added dropwise and the reactionmixture was stirred at 0° C. for 30 min. Thereafter, 2.39 ml (38.45mmol) of iodomethane were added dropwise, and the reaction mixture wasbrought to RT and stirred for 1 h. For workup, water (200 ml) was addedat 0° C. and the mixture was extracted three times with ethyl acetate.The combined organic phases were washed with water and saturated sodiumchloride solution, dried over magnesium sulphate, filtered andconcentrated. The residue was subjected to extractive stirring in MTBE,and the solid was filtered off, washed with MTBE and dried under highvacuum. This gave 1.89 g (62% of theory) of the title compound. Thecrude product was converted without further purification.

LC-MS (Method 1): R_(t)=0.78 min; MS (ESIpos): m/z=199 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.23 (s, 6H), 6.98-7.05 (m, 4H).

Example 85A 1,3-dimethyl-5-nitro-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide

1.88 g (9.52 mmol) of 1,3-dimethyl-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide from Example 84A were initially charged in 8 ml of aceticacid, then 0.60 ml (9.52 mmol) of conc. nitric acid was added dropwiseand the reaction mixture was stirred at RT for 1 h. For workup, thereaction mixture was added to ice-water, and the precipitated solid wasfiltered off with suction, washed with water and dried under reducedpressure at 50° C. This gave 2.17 g (93% of theory) of the titlecompound.

LC-MS (Method 1): R_(t)=0.81 min; MS (ESIpos): m/z=244 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.37-3.42 (m, 6H), 7.23 (d, 1H), 7.92(d, 1H), 8.03 (dd, 1H).

Example 86A 1,3-dimethyl-1,3-dihydro-2,1,3-benzothiadiazol-5-amine2,2-dioxide

The preparation and purification of the target compound were analogousto Example 33A, with a reaction time of 16 h. Proceeding from 2.17 g(8.92 mmol) of 1,3-dimethyl-5-nitro-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide from Example 85A, 851 mg (44% of theory) of the titlecompound were obtained.

LC-MS (Method 1): R_(t)=0.31 min; MS (ESIpos): m/z=214 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.07 (s, 3H), 3.10 (s, 3H), 4.89-4.99(m, 2H), 6.18-6.24 (m, 2H), 6.70 (d, 1H).

Example 87A ethyl1-(1,3-dimethyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

1.03 g (3.99 mmol) of ethyl3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate and 851 mg (3.99 mmol) of1,3-dimethyl-1,3-dihydro-2,1,3-benzothiadiazol-5-amine 2,2-dioxide fromExample 86A were initially charged in 30 ml of ethanol and heated toreflux for 2 h. Subsequently, at RT, 448 mg (3.99 mmol) of potassiumtert-butoxide were added and the mixture was stirred at RT for 16 h andat reflux for 5 h. For workup, the reaction mixture was acidified with1N hydrochloric acid, and the solid formed was filtered off, washed withwater and ethyl acetate and then dried under reduced pressure at 50° C.This gave 1.36 g (84% purity, 75% of theory) of the title compound.

LC-MS (Method 1): R_(t)=0.74 min; MS (ESIpos): m/z=381 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.20-1.24 (m, 3H), 3.25 (s, 3H), 3.30(s, 3H), 4.17 (q, 2H), 7.12-7.19 (m, 2H), 7.24-7.28 (m, 1H), 8.29 (s,1H), 11.71 (br.s, 1H).

Example 88A ethyl1-(1,3-benzothiazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation of the target compound was analogous to Example 76A,using 1.00 g (6.65 mmol) of 1,3-benzothiazol-6-amine and 1.72 g (6.65mmol) of ethyl 3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate. Forworkup, the reaction mixture was admixed with water and 1N hydrochloricacid, and the precipitated solid was filtered off with suction, washedwith ethyl acetate and dried at 50° C. under reduced pressure. This gave1.85 g (87% of theory) of the title compound.

LC-MS (Method 1): R_(t)=0.61 min; MS (ESIpos): m/z=318 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 4.18 (q, 2H), 7.67 (dd,1H), 8.20 (d, 1H), 8.36 (d, 1H), 8.42 (s, 1H), 9.53 (s, 1H), 11.76 (s,1H).

Example 89A 1-methyl-6-nitro-3,4-dihydroquinolin-2(1H)-one

Under argon, 1.00 g (5.20 mmol) of 6-nitro-3,4-dihydroquinolin-2(1H)-one[for preparation see: WO 2006/71940, 416] was initially charged in 148ml of THF, then 229 mg (5.72 mmol) of sodium hydride (60% in mineraloil) were added at 0° C. and the mixture was stirred for 30 min.Thereafter, 0.36 ml (5.72 mmol) of iodomethane was added dropwise andthe reaction mixture was stirred at RT overnight. For workup, thereaction mixture was diluted with ethyl acetate, and the organic phasewas washed twice with saturated sodium hydrogencarbonate solution, driedover magnesium sulphate, filtered and concentrated. The residue wasstirred with ethanol, and the solid was filtered off, washed withethanol and dried under high vacuum overnight. This gave 535 mg (50% oftheory) of the title compound. The crude product was converted withoutfurther purification.

LC-MS (Method 3): R_(t)=0.88 min; MS (ESIpos): m/z=207 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.60-2.66 (m, 2H), 3.02 (t, 2H), 3.31(s, 3H), 7.26-7.32 (m, 1H), 8.12-8.20 (m, 2H).

Example 90A 6-amino-1-methyl-3,4-dihydroquinolin-2(1H)-one

1.10 g (5.33 mmol) of the nitro compound from Example 89A were initiallycharged in 36 ml of ethanol, then 170 mg (0.16 mmol) of palladium (10%on activated carbon) were added and the mixture was hydrogenated atstandard hydrogen pressure overnight. Subsequently, the reaction mixturewas filtered through kieselguhr, the residue was washed with ethanol andthe filtrate was concentrated. This gave 936 mg (99% of theory) of thetarget compound. The crude product was converted without furtherpurification.

LC-MS (Method 2): R_(t)=0.73 min; MS (ESIpos): m/z=177 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.43 (t, 2H), 2.69 (t, 2H), 3.16 (s,3H), 4.79-4.90 (m, 2H), 6.41-6.47 (m, 2H), 6.77 (d, 1H).

Example 91A ethyl1-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the target compound were analogousto Example 31A. Proceeding from 935 mg (5.30 mmol) of6-amino-1-methyl-3,4-dihydroquinolin-2(1H)-one from Example 90A[synthesis described in: WO 2003/72553, page 150-151] and 1.37 g (5.30mmol) of ethyl 3-ethoxy-2-[(ethoxycarbonyl)-carbamoyl]acrylate, 1.33 g(73% of theory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.65 min; MS (ESIpos): m/z=344 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 2.56-2.61 (m, partlyconcealed by DMSO signal), 2.87-2.94 (m, 2H), 3.28 (s, 3H), 4.17 (q,2H), 7.20 (d, 1H), 7.35-7.41 (m, 2H), 8.25 (s, 1H), 11.68 (s, 1H).

Example 92A ethyl1-(1-methyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

916 mg (3.53 mmol) of ethyl3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate and 630 mg (3.53 mmol) of6-amino-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one [for preparationsee: WO 2007/93904; p. 22, step 3] were initially charged in 20 ml ofethanol and heated to reflux for 1 h. Thereafter, at RT, 397 mg (3.53mmol) of potassium tert-butoxide were added and the reaction mixture wasstirred at RT for 16 h and at reflux for 3 h. For workup, the mixturewas acidified with 1N hydrochloric acid at RT, and the solid formed wasfiltered off, washed with MTBE and then dried under reduced pressure at50° C. This gave 1.11 g (90% of theory) of the title compound.

LC-MS (Method 1): R_(t)=0.58 min; MS (ESIpos): m/z=346 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 3.3 (s, partlyconcealed by water signal), 4.17 (q, 2H), 5.29 (s, 2H), 7.21 (d, 1H),7.40-7.44 (m, 1H), 7.48-7.54 (m, 1H), 8.27 (s, 1H), 11.70 (s, 1H).

Example 93A ethyl1-(4-methylquinolin-7-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the target compound were analogousto Example 31A. Proceeding from 987 mg (5.31 mmol) of4-methylquinolin-7-amine [for preparation see: Nasr, M. et al., J. Med.Chem. 1988, vol. 31 (7), p. 1347-1351] and 1.37 g (5.31 mmol) of ethyl3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate, 745 mg (43% of theory)of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.63 min; MS (ESIpos): m/z=326 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.24 (t, 3H), 2.88 (s, 3H), 4.19 (q,2H), 7.79 (d, 1H), 7.93 (dd, 1H), 8.32 (d, 1H), 8.41 (d, 1H), 8.50 (s,1H), 9.06 (d, 1H), 11.82 (s, 1H).

Example 94A ethyl1-(imidazo[1,2-a]pyridin-7-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the target compound were analogousto Example 31A. Proceeding from 500 mg (3.75 mmol) ofimidazo[1,2-a]pyridin-7-amine [for preparation see: Tetrahedron, 2002,vol. 58 (2), p. 295-308] and 973 mg (3.75 mmol) of ethyl3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate, 1.11 g (94% of theory)of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.19 min; MS (ESIpos): m/z=301 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.24 (t, 3H), 4.21 (q, 2H), 7.60 (d,1H), 8.21 (d, 2H), 8.39 (s, 1H), 8.48 (s, 1H), 8.96 (d, 1H), 11.91 (s,1H).

Example 95A ethyl1-(6-fluoro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation of the target compound was analogous to Example 31A,using 660 mg (3.38 mmol) of5-amino-6-fluoro-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-one fromExample 19A and 877 mg (3.38 mmol) of ethyl3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate. The resulting crudeproduct was purified by means of flash silica gel chromatography(dichloromethane/methanol gradient 54:1-20:1) to obtain 437 mg (36% oftheory) of the title compound.

LC-MS (Method 1): R_(t)=0.62 min; MS (ESIpos): m/z=363 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 3.32 (s, 3H), 3.36 (s,3H), 4.18 (q, 2H), 7.40 (d, 1H), 7.48 (d, 1H), 8.40 (s, 1H), 11.85 (s,1H).

Example 96A (3-chloro-4-methyl-2-thienyl)methanol

To a solution of borane-tetrahydrofuran complex (1M in THF, 3.40 ml,3.40 mmol) were added, at RT under argon, 200 mg (1.13 mmol) of3-chloro-4-methylthiophene-2-carboxylic acid in portions and thereaction mixture was stirred at RT for 1 h. Subsequently, the reactionmixture was cautiously added to 1N hydrochloric acid until the evolutionof gas had ended. The whole mixture was separated by preparative HPLC(Method 8). This gave 115 mg (62% of theory) of the title compound.

GC-MS (Method 6): R_(t)=4.00 min; EI⁺: m/z=162 (M)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.12 (s, 3H), 4.58 (d, 2H), 5.57 (t,1H), 7.25 (s, 1H).

Example 97A 4,6-difluoroindan-1-ol (racemate)

146.3 mg (3.87 mmol) of sodium borohydride were added to a solution of1.00 g (5.95 mmol) of 4,6-difluoro-2,3-dihydro-1H-inden-1-one in 15 mlof ethanol at RT and the reaction mixture was stirred at RT overnight.The mixture was admixed with ethyl acetate and water and shakenvigorously. The organic phase was removed, washed with a saturatedammonium chloride solution and a saturated sodium chloride solution,dried over magnesium sulphate and freed of the solvent on a rotaryevaporator. The residue was dried briefly under HV. This gave 950 mg(94% of theory) of the title compound.

GC-MS (Method 6): R_(t)=3.35 min; MS (CI-pos): m/z=170 (M)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.78-1.88 (m, 1H), 2.35-2.44 (m, 1H),2.67 (dt, 1H), 2.90 (ddd, 1H), 5.05 (q, 1H), 5.49 (d, 1H), 6.99 (dd,1H), 7.04 (td, 1H).

Example 98A 6-fluoro-4-(trifluoromethyl)indan-1-ol racemate)

23.3 mg (0.62 mmol) of sodium borohydride were added to a solution of207 mg (0.95 mmol) of6-fluoro-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-one (preparation:see US2011/53974, Page 77, Example 61C) in 6 ml of ethanol at RT and thereaction mixture was stirred at RT overnight. The mixture was admixedwith ethyl acetate and 1N hydrochloric acid and shaken vigorously. Theorganic phase was removed, washed with 1N hydrochloric acid and thenwith a saturated sodium chloride solution, dried over sodium sulphateand freed completely of the solvent on a rotary evaporator. This gave203 mg (97% of theory) of the title compound.

GC-MS (Method 6): R_(t)=3.19 min; MS (CI-pos): m/z=220 (M)⁺.

¹H NMR (400 MHz, CD₂Cl₂)): δ [ppm]=1.84-1.96 (m, 1H), 2.43-2.54 (m, 1H),2.82 (dt, 1H), 3.02-3.14 (m, 1H), 5.14 (t, 1H), 7.17 (d, 1H), 7.21 (d,1H).

Example 99A 7-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-ol (racemate)

Analogously to Example 98A, 388 mg (1.92 mmol) of7-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-one (preparation: see US2011/53974, Page 56, Example 47E) were reduced with sodium borohydride.This gave 210 mg (51% of theory) of the title compound.

GC-MS (Method 6): R_(t)=3.80 min; MS (CI-pos): m/z=204 (M)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=4.38 (dd, 1H), 4.66 (dd, 1H), 5.33(dd, 1H), 5.72-5.91 (br. m, 1H), 7.07 (t, 1H), 7.52 (d, 1H), 7.66 (d,1H).

Example 100A 6-methylindan-1-ol (racemate)

Analogously to Example 97A, 1.00 g (6.84 mmol) of6-methyl-2,3-dihydro-1H-inden-1-one was reduced with sodium borohydride.This gave 950 mg (94% of theory) of the title compound.

GC-MS (Method 6): R_(t)=3.89 min; MS (CI-pos): m/z=148 (M)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.74 (dddd, 1H), 2.25-2.35 (m, 1H),2.64 (dt, 1H), 2.84 (ddd, 1H), 4.99 (q, 1H), 5.14 (d, 1H), 6.99 (br. d,1H), 7.08 (d, 1H), 7.12 (s, 1H).

Example 101A tert-butyl6-[5-(ethoxycarbonyl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate

A suspension of 8.00 g (24.2 mmol) of the compound from Example 36A and30 mg (0.24 mmol) of DMAP in 500 ml of DMF and 100 ml of dichloromethanewas admixed at RT with 6.12 ml (26.6 mmol) of di-tert-butyl di-carbonateand stirred at RT overnight. For workup, 1.6 l of water were added andthe mixture was extracted three times with ethyl acetate. The combinedorganic phases were washed twice with water, dried over sodium sulphateand concentrated on a rotary evaporator. The residue was stirred withdiethyl ether, and the precipitated product was isolated by filtrationand dried under HV. This gave 6.00 g (58% of theory) of the titlecompound.

LC-MS (Method 4): R_(t)=1.80 min; m/z=431 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 1.58 (s, 9H), 4.17 (q,2H), 7.28-7.40 (m, 2H), 7.84 (d, 1H), 8.25 (s, 1H), 11.65 (s, 1H)(methyl group probably under the DMSO signal).

Example 102A 5-methoxyindan-1-ol (racemate)

Analogously to Example 97A, 1.00 g (6.17 mmol) of5-methoxy-2,3-dihydro-1H-inden-1-one was reduced with sodiumborohydride. This gave 930 mg (80% purity, 73% of theory) of the titlecompound.

GC-MS (Method 6): R_(t)=4.70 min; MS (CI-pos): m/z=164 (M)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.71-1.82 (m, 1H), 2.25-2.34 (m, 1H),2.61-2.72 (m, 1H), 2.83-2.93 (m, 1H), 3.72 (s, 3H), 4.97 (q, 1H), 5.05(d, 1H), 6.71-6.76 (m, 1H), 6.77 (br. s, 1H), 7.21 (d, 1H).

Example 103A 4-methoxyindan-1-ol (racemate)

Analogously to Example 97A, 1.00 g (6.17 mmol) of4-methoxy-2,3-dihydro-1H-inden-1-one was reduced with sodiumborohydride. This gave 910 mg (90% of theory) of the title compound.

GC-MS (Method 6): R_(t)=4.65 min; MS (CI-pos): m/z=164 (M)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.68-1.80 (m, 1H), 2.25-2.35 (m, 1H),2.54-2.62 (m, 1H), 2.83 (ddd, 1H), 3.76 (s, 3H), 5.02 (q, 1H), 5.18 (d,1H), 6.80 (d, 1H), 6.93 (d, 1H), 7.17 (t, 1H).

Example 104A methyl (2E)-3-[4-chloro-2-(trifluoromethyl)phenyl]acrylate

A mixture of 8.00 g (26.1 mmol) of4-chloro-1-iodo-2-(trifluoromethyl)benzene, 3.76 ml (41.8 mmol) ofmethyl acrylate, 7.47 g (26.9 mmol) of tetra-n-butylammonium chloride,117 mg (0.52 mmol) of palladium(II) acetate and 7.22 g (52.2 mmol) ofpotassium carbonate in 80 ml of DMF was stirred at RT for 3 days. Themixture was diluted with 1 l of diethyl ether and washed three timeswith 200 ml each time of water. The organic phase was dried over sodiumsulphate and concentrated on a rotary evaporator. The residue solidifiedafter a while. This gave 6.65 g (92% of theory) of the title compound.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.76 (s, 3H), 6.81 (d, 1H), 7.79 (dq,1H), 7.84 (dd, 1H), 7.91 (d, 1H), 8.12 (d, 1H).

Example 105A methyl 3-[4-chloro-2-(trifluoromethyl)phenyl]propanoate

6.65 g (25.1 mmol) of the compound from Example 104A were hydrogenatedunder standard hydrogen pressure in 250 ml of ethyl acetate in thepresence of 2 g of palladium (10% on carbon) for 2 days. The catalystwas removed by filtration through kieselguhr and the filtrate wasconcentrated on a rotary evaporator. This gave 5.26 g of the titlecompound in about 75% purity (59% of theory).

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.62-2.68 (m, 2H), 3.01 (t, 2H), 3.61(s, 3H), 7.56 (d, 1H), 7.69-7.76 (m, 2H).

Example 106A 3-[4-chloro-2-(trifluoromethyl)phenyl]propanoic acid

A solution of 5.26 g (19.7 mmol) of the compound from Example 105A in150 ml of methanol was admixed with 59.2 ml (59.2 mmol) of 1M sodiumhydroxide solution and stirred at RT for 2 h. The methanol was removedon a rotary evaporator. The remaining aqueous residue was diluted with600 ml of water and filtered. The filtrate was acidified with 1Mhydrochloric acid. The precipitated solid was filtered off with suction,washed with water and dried under HV. This gave 4.45 g of the titlecompound in about 90% purity (80% of theory).

LC-MS (Method 5): R_(t)=1.02 min; MS (ESIneg): m/z=251 (M−H)⁻.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.52-2.58 (m, 2H, partly hidden underthe DMSO signal), 2.97 (t, 2H), 7.56 (d, 1H), 7.68-7.76 (m, 2H), 12.32(br.s, 1H).

Example 107A 6-chloro-4-(trifluoromethyl)indan-1-one

4.08 g (92% purity, 14.8 mmol) of the compound from Example 106A wereadmixed with 44 ml of chlorosul-phonic acid while cooling with ice andthen stirred at RT for 5 h. Subsequently, the reaction mixture wascautiously added dropwise to 600 g of crushed ice (very exothermic). Themixture was extracted three times with dichloromethane. The combinedorganic phases were washed twice with a 1M sodium carbonate solution,dried over sodium sulphate and concentrated on a rotary evaporator. Theresidue was dried only briefly under HV. This gave 2.38 g of the titlecompound in about 92% purity (63% of theory).

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.73-2.82 (m, 2H), 3.19-3.28 (m, 2H),7.96 (s, 1H), 8.13 (s, 1H).

Example 108A 6-chloro-4-(trifluoromethyl)indan-1-ol (racemate)

Analogously to Example 98A, 2.38 g (10.1 mmol) of6-chloro-4-(trifluoromethyl)indan-1-one from Example 107A were reducedwith sodium borohydride. This gave 1.97 g (82% of theory) of the titlecompound.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.79-1.92 (m, 1H), 2.35-2.47 (m, 1H),2.84 (dt, 1H), 2.98-3.10 (m, 1H), 5.09 (q, 1H), 5.58 (d, 1H), 7.64 (br.d, 2H).

Example 109A methyl (2E)-3-[4-bromo-2-(trifluoromethyl)phenyl]acrylate

Analogously to Example 104A, 8.00 g (22.8 mmol) of4-bromo-1-iodo-2-(trifluoromethyl)benzene were reacted with 3.29 ml(36.5 mmol) of methyl acrylate and the product was isolated. The crudeproduct was purified by means of chromatography on silica gel (eluent:cyclohexane/ethyl acetate 10:1). This gave 5.70 g (81% of theory) of thetitle compound.

GC-MS (Method 6): R_(t)=4.75 min; MS (CI-pos): m/z=308/310 (M)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.76 (s, 3H), 6.82 (d, 1H), 7.77 (dq,1H), 7.94-8.07 (m, 3H).

Example 110A methyl 3-[4-bromo-2-(trifluoromethyl)phenyl]propanoate

5.70 g (18.4 mmol) of the compound from Example 109A were firsthydrogenated analogously to Example 105A with palladium (10% on carbon)under standard hydrogen pressure. Monitoring the reaction by means ofLC-MS showed no reduction of the double bond, but about 25%debromination. The hydrogenation was stopped, the catalyst was filteredoff and the solvent was removed on a rotary evaporator. The reactantthus re-covered (5.0 g) was heated in 30 ml of toluene with 87 mg (0.16mmol) of [Rh{(S,S)-Phebox-iPr}(OAc)₂].H₂O (preparation: see H. Nishiyamaet al, Chem. Eur. J. 2006, 12 (1), 63-71, Example 3a) to 60° C. andadmixed at this temperature with 3.89 ml (24.26 mmol) ofmethyldiethoxysilane. The mixture was stirred further at 60° C. for 4 h,then at reflux temperature overnight. After cooling to RT, the mixturewas admixed with 50 ml of 1N hydrochloric acid and extracted with 150 mlof ethyl acetate. The organic phase was washed twice with water, twicewith a saturated sodium hydrogencarbonate solution and once with asaturated sodium chloride solution, dried over sodium sulphate andconcentrated on a rotary evaporator. The residue corresponded to thetitle compound in about 80% purity (5.84 g, 93% of theory) and wasconverted further without purification.

GC-MS (Method 6): R_(t)=4.42 min; MS (CI-pos): m/z=310/312 (M)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=2.54-2.64 (m, 2H), 3.07 (t, 2H), 3.66(s, 3H), 7.27 (d, 1H), 7.63 (d, 1H), 7.78 (d, 1H).

Example 111A 3-[4-bromo-2-(trifluoromethyl)phenyl]propanoic acid

Analogously to Example 106A, 5.60 g (18 mmol) of the compound fromExample 110A were converted and isolated. This gave 3.42 g (54% oftheory) of the title compound in about 85% purity.

LC-MS (Method 4): R_(t)=2.25 min; MS (ESIpos): m/z=295/297 (M−H)⁻.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.52-2.58 (m, 2H, partly hidden underthe DMSO signal), 2.95 (t, to 2H), 7.49 (d, 1H), 7.81-7.88 (m, 2H),12.37 (br.s, 1H).

Example 112A 6-bromo-4-(trifluoromethyl)indan-1-one

Analogously to Example 107A, 3.42 g (85% purity, 9.8 mmol) of thecompound from Example 111A were converted and isolated. This gave 2.10 g(69% of theory) of the title compound in about 90% purity.

GC-MS (Method 6): R_(t)=4.34 min; MS (CI-pos): m/z=278/280 (M)⁺.

¹H NMR (400 MHz, CDCl₃): δ [ppm]=2.75-2.82 (m, 2H), 3.23-3.31 (m, 2H),7.96 (s, 1H), 8.05 (s, 1H).

Example 113A 6-bromo-4-(trifluoromethyl)indan-1-ol (racemate)

A solution of 500 mg (1.79 mmol) of the compound from Example 112A in3.9 ml of ethanol was admixed with 44.0 mg (1.16 mmol) of sodiumborohydride and stirred at RT overnight. 3 ml of 1N hydrochloric acidwere added, and the mixture was stirred for a few minutes, thenseparated completely by HPLC (Method 7). The product-containingfractions were concentrated fully in vacuo and the residue was driedunder HV. This gave 352 mg (92% of theory) of the title compound.

GC-MS (Method 6): R_(t)=4.58 min; MS (CI-pos): m/z=280/282 (M)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.79-1.90 (m, 1H), 2.35-2.46 (m, 1H),2.82 (dt, 1H), 2.97-3.07 (m, 1H), 5.09 (q, 1H), 5.57 (dd, 1H), 7.74(br.s, 1H), 7.77 (br.s, 1H).

Example 114A 4,6-dichloroindan-1-ol (racemate)

Analogously to Example 98A, 1.25 g (6.22 mmol) of4,6-dichloroindan-1-one was reduced with sodium borohydride and theproduct was isolated. This gave 1.20 g (95% of theory) of the titlecompound.

MS (Method 26 DCI/NH₃): m/z=202 (M⁺)

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.75-1.90 (m, 1H), 2.30-2.44 (m, 1H),2.64-2.78 (m, 1H), 2.85-2.98 (m, 1H), 5.09 (q, 1H), 5.53 (d, 1H), 7.32(s, 1H), 7.44 (d, 1H).

Example 115A 1-[2-meth-3-(trifluoromethyl)phenyl]ethanol

4.25 ml of a solution of methylmagnesium bromide (3M in diethyl ether,12.75 mmol) were added dropwise to a solution of 2.00 g (10.6 mmol) of2-methyl-3-(trifluoromethyl)benzaldehyde in 50 ml of diethyl ether, inthe course of which the reaction mixture warmed up to refluxtemperature. After addition had ended, the reaction mixture was heatedto reflux for a further hour. After cooling to RT, small pieces of icewere added, then 6N hydrochloric acid was added dropwise until theprecipitate which had formed dissolved again. The phases were separated.The aqueous phase was extracted once more with diethyl ether. Thecombined organic phases were dried over magnesium sulphate andconcentrated on a rotary evaporator. This gave 2.40 g of the titlecompound (100% of theory, according to NMR still contains about 10%diethyl ether).

¹H NMR (500 MHz, CDCl₃): δ [ppm]=1.48 (d, 3H), 5.25 (q, 1H), 7.32 (t,1H), 7.56 (d, 1H), 7.76 (d, 1H).

Example 116A 1-[2-chloro-3-(trifluoromethyl)phenyl]ethanol

Analogously to Example 15A, 2.00 g (9.59 mmol) of2-methyl-3-(trifluoromethyl)benzaldehyde were reacted withmethylmagnesium bromide. This gave 2.40 g of the title compound (89% oftheory, according to NMR still contains about 20% diethyl ether).

¹H NMR (500 MHz, CDCl₃): δ [ppm]=1.51 (d, 3H), 5.41 (q, 1H), 7.41 (t,1H), 7.62 (d, 1H), 7.85 (d, 1H).

Example 117A ethyl1-(1-ethyl-2-methyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

1.04 g (4.03 mmol) of ethyl3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate and 1.00 g (4.03 mmol) of1-ethyl-2-methyl-1H-benzimidazol-5-amine dihydrochloride were initiallycharged in 30 ml of ethanol, then 1.24 ml (8.87 mmol) of triethylaminewere added and the mixture was heated to reflux for 2 h. Thereafter, atRT, 452 mg (4.03 mmol) of potassium tert-butoxide were added and thereaction mixture was first stirred further at RT overnight, then heatedto reflux and stirred at this temperature overnight. For workup, thereaction mixture was admixed with water and acidified with 1Nhydrochloric acid. The mixture was concentrated to dryness, and theresidue was stirred with dichloromethane/methanol (1:1) and filtered.The filtrate was concentrated again, the residue was stirred withMTBE/ethyl acetate and the solid formed was filtered off. After dryingunder HV, 1.07 g (87% pure, 68% of theory) of the target compound wereobtained.

LC-MS (Method 2): R_(t)=1.06 min; MS (ESIpos): m/z=343 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 1.41 (t, 3H), 2.84 (s,3H), 4.18 (q, 2H), 4.47 (q, 2H), 7.64-7.70 (m, 1H), 7.99-8.02 (m, 1H),8.06 (d, 1H), 8.35 (s, 1H), 11.75 (s, 1H).

Example 118A ethyl1-(1-cyclohexyl-2-methyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

0.86 g (3.31 mmol) of ethyl3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate and 1.00 g (3.31 mmol) of1-cyclohexyl-2-methyl-1H-benzimidazol-5-amine dihydrochloride wereinitially charged in 25 ml of ethanol and the mixture was heated toreflux for 2 h. Subsequently, at RT, 371 mg (3.31 mmol) of potassiumtert-butoxide were added and the reaction mixture was stirred at RTovernight and at reflux for 5 days. For workup, the reaction mixture wasadmixed with water, acidified with 1N hydrochloric acid and thenconcentrated on a rotary evaporator. The residue was stirred indichloromethane/methanol (1:1) and the insoluble residues were filteredoff. The filtrate was concentrated and admixed with ethanol, and thesolid formed was filtered off and dried. This gave 1.85 g of the titlecompound as a crude product, which was converted without furtherpurification.

LC-MS (Method 1): R_(t)=0.72 min; MS (ESIpos): m/z=397 (M+H)⁺.

Example 119A ethyl1-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

2.00 g (11.2 mmol) of 7-amino-4-methyl-2H-1,4-benzoxazin-3(4H)-one and2.65 g (10.2 mmol) of ethyl3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate were initially charged in100 ml of ethanol and the mixture was heated to reflux for 2 h. Aftercooling to RT, 1.15 g (10.2 mmol) of potassium tert-butoxide were addedand the reaction mixture was stirred further at RT for two days and thenat reflux temperature for 1 h. For workup, the reaction mixture wasdiluted with water and acidified with 1M hydrochloric acid. The solidformed was filtered off, washed with water and dried under HV. This gave2.79 mg (70% of theory) of the title compound.

LC-MS (Method 3): R_(t)=0.76 min; MS (ESIpos): m/z=346 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 4.17 (q, 2H), 4.71 (s,2H), 7.18-7.23 (m, 2H), 7.28 (d, 1H), 8.22 (s, 1H), 11.68 (s, 1H).

Example 120A 8-chloro-3,4-dihydro-1H-isochromen-4-ol

To a solution of 270 mg (1.48 mmol) of 8-chloro-1H-isochromen-4(3H)-one(reactant prepared in house, not described in literature but availablefrom ACD supplier with catalogue number and CAS No.) in 5 ml of methanolwere added, at RT, 224 mg (5.91 mmol) of sodium borohydride, and themixture was stirred at RT for 1 h. Subsequently, 5 ml of aqueous 1Nhydrochloric acid were added, and the mixture was stirred for a further10 min and then separated by means of preparative HPLC (Method 15). Thesuitable fractions were freed of acetonitrile on a rotary evaporator at130 mbar and the remaining aqueous phase was extracted three times withdichloromethane. The combined organic phases were dried over sodiumsulphate and concentrated on a rotary evaporator at 130 mbar. This gave400 mg of the title compound, which according to NMR still containsacetonitrile and dichloromethane. It was used as such for thepreparation of Example 302.

LC/MS (Method 4): R_(t)=1.69 min; m/z=167 (M-OH)⁺

¹H NMR (400 MHz, CDCl₃): δ [ppm]=2.57 (br. s, 1H), 3.85 (dd, 1H), 4.09(dd, 1H), 4.56 (br. s., 1H), 4.62 (d, 1H), 4.89 (d, 1H), 7.22-7.35 (m,2H), 7.39 (d, 1H).

WORKING EXAMPLES Example 1 ethyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)-benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

To a solution of 14.95 g (43.42 mmol) of ethyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 2A in DMF (200 ml) were added 12.00 g (86.84 mmol) ofpotassium carbonate, 12.09 g (47.76 mmol) of2-methyl-3-(trifluoromethyl)benzyl bromide and 0.721 g (4.34 mmol) ofpotassium iodide, and the reaction mixture was left to stir at 80° C.for 3 h. Subsequently, the mixture was cooled to RT, water was added andthe precipitate formed was filtered off. The solid was washedsuccessively with water and MTBE, and dried under reduced pressure at50° C. This gave 21.04 g (94% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.07 min; m/z=517 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 2.46 (s, 3H), 3.34 (s,3H), 3.37 (s, 3H), 4.20 (q, 2H), 5.09 (s, 2H), 7.23-7.30 (m, 2H),7.32-7.43 (m, 3H), 7.58-7.62 (m, 1H), 8.42 (s, 1H).

In analogy to Example 1, the above-described1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxylic esters(uracil-5-carboxylic esters) were used to obtained, by reaction with therespective benzyl chlorides or benzyl bromides in the presence ofpotassium carbonate and potassium iodide, the benzyl-substituted uracilcompounds which follow. A difference is that 1-3 equivalents ofpotassium carbonate and 0.1 to 2 equivalents of potassium iodide mayalso be used. Given compounds of sufficient solubility, acetonitrile wasused as a solvent in some cases.

Example 2 ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 1. Proceeding from 200 mg (0.58 mmol) of ethyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 2A and 175 mg (0.64 mmol) of2-chloro-3-(trifluoromethyl)benzyl bromide, 234 mg (73% of theory) ofthe title compound were obtained.

LC-MS (Method 1): R_(t)=1.08 min; m/z=537 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 3.34 (s, 3H), 3.37 (s,3H), 4.20 (d, 2H), 5.16 (s, 2H), 7.27 (s, 2H), 7.39-7.42 (m, 1H),7.50-7.60 (m, 2H), 7.78-7.83 (m, 1H), 8.44 (s, 1H).

Example 3 ethyl3-(2,3-dichlorobenzyl)-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 1, using acetonitrile as a solvent. Proceeding from 200 mg (0.58mmol) of ethyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 2A and 125 mg (0.64 mmol) of 2,3-dichlorobenzyl chloride,241 mg (79% of theory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.05 min; m/z=503 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 3.34 (s, 3H), 3.37 (s,3H), 4.20 (q, 2H), 5.11 (s, 2H), 7.20-7.29 (m, 3H), 7.31-7.36 (m, 1H),7.39-7.41 (m, 1H), 7.56-7.60 (m, 1H), 8.43 (s, 1H).

Example 4 ethyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-fluoro-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 1. Proceeding from 200 mg (0.58 mmol) of ethyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 2A and 164 mg (0.64 mmol) of2-fluoro-3-(trifluoromethyl)benzyl bromide, 162 mg (53% of theory) ofthe title compound were obtained.

LC-MS (Method 1): R_(t)=1.13 min; m/z=521 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ=1.23 (t, 3H), 3.33 (s, 3H), 3.34 (s, 3H),4.20 (d, 2H), 5.15 (s, 2H), 7.19-7.31 (m, 2H), 7.31-7.44 (m, 2H), 7.68(d, 2H), 8.40 (s, 1H).

Example 5 ethyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[3-fluoro-2-(trifluoromethyl)-benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 1. Proceeding from 179 mg (0.52 mmol) of ethyl1-(4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 2A and 147 mg (0.57 mmol) of 3-fluoro-2-trifluorobenzylbromide, 207 mg (74% of theory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.12 min; m/z=521 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 3.34 (s, 3H), 3.37 (s,3H), 4.20 (q, 2H), 5.21 (s, 2H), 7.17-7.22 (m, 1H), 7.22-7.30 (m, 2H),7.37-7.44 (m, 2H), 7.63-7.71 (m, 1H), 8.45 (s, 1H).

Example 6 ethyl3-(2-chloro-3,6-difluorobenzyl)-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

150 mg (0.43 mmol) of the compound from Example 5A were initiallycharged in acetonitrile (2.06 ml), together with 417 mg of the boronicester from Example 3A (60% purity, 0.87 mmol) and 0.18 ml (1.30 mmol) oftriethylamine. Subsequently, molecular sieve (3 Å), 118 mg (0.65 mmol)of copper(II) acetate and 0.13 ml (1.83 mmol) of DMSO were added and thereaction mixture was stirred in a closed vessel at 80° C. for 3 days.For workup, the reaction mixture was admixed with ethyl acetate, thenwashed twice with hydrochloric acid (1M), once with saturated sodiumhydrogencarbonate solution and once with saturated sodium chloridesolution. The organic phase was then dried over magnesium sulphate,filtered and concentrated. The residue was stirred with methanol, andthe solid was filtered off with suction, washed with methanol and driedat 50° C. under reduced pressure. This gave 114 mg (84% purity, 44% oftheory) of the title compound.

LC-MS (Method 2): R_(t)=2.06 min; m/z=505 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 4.16 (q, 2H), 5.21 (s,2H), 7.16 (d, 1H), 7.22-7.31 (m, 2H), 7.34 (s, 1H), 7.38-7.48 (m, 1H),8.36 (s, 1H).

Example 7 ethyl3-(3-chloro-2-methylbenzyl)-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

150 mg (0.46 mmol) of the compound from Example 7A were initiallycharged in acetonitrile (4.00 ml), together with 267 mg of the boronicester from Example 3A (0.93 mmol) and 0.19 ml (1.39 mmol) oftriethylamine. Subsequently, molecular sieve (3 Å), 126 mg (0.69 mmol)of copper(II) acetate and 0.13 ml (1.83 mmol) of DMSO were added and thereaction mixture was stirred in a closed vessel at 80° C. for 1 day. Forworkup, the mixture was admixed with ethyl acetate, then washed twicewith 1M hydrochloric acid, once with saturated sodium hydrogencarbonatesolution and once with saturated sodium chloride solution. The organicphase was then dried over magnesium sulphate, filtered and concentrated.The residue was stirred with MTBE, and the solid was filtered off withsuction and dried at 50° C. under reduced pressure. This solid waspurified by means of preparative HPLC (Method 8). This gave 78 mg (35%of theory) of the title compound.

LC-MS (Method 3): R_(t)=1.34 min; m/z=483 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 2.41 (s, 3H), 3.34 (s,3H), 3.37 (s, 3H), 4.19 (q, 2H), 5.05 (s, 2H), 7.05 (d, 1H), 7.17 (t,1H), 7.22-7.30 (m, 2H), 7.35 (d, 1H), 7.41 (d, 1H), 8.40 (s, 1H).

Example 8 ethyl3-[2,3-bi(trifluoromethyl)benzyl]-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

150 mg (0.37 mmol) of the compound from Example 10A were initiallycharged in acetonitrile (4.00 ml), together with 248 mg of the boronicester from Example 3A (85% purity, 0.73 mmol) and 0.15 ml (1.10 mmol) oftriethylamine. Subsequently, molecular sieve (3 Å), 100 mg (0.54 mmol)of copper(II) acetate and 0.13 ml (1.83 mmol) of DMSO were added and thereaction mixture was agitated in a closed vessel at 80° C. for 3 days.For workup, the reaction mixture was diluted with ethyl acetate, thenwashed twice with 1M hydrochloric acid and once each with saturatedsodium hydrogencarbonate solution and saturated sodium chloridesolution. The organic phase was then dried over magnesium sulphate,filtered and concentrated. The residue was separated by means ofpreparative HPLC (Method 8). The product-containing fractions werepartly concentrated on a rotary evaporator. The solid which precipitatedout was filtered off, washed with water and dried under high vacuum.This gave 127 mg (61% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.05 min; m/z=571 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 3.2-3.4 (2 s, partlyconcealed by water signal), 4.20 (q, 2H), 5.25 (br.s, 2H), 7.26 (q, 2H),7.39 (s, 1H), 7.73 (d, 1H), 7.85 (t, 1H), 7.98 (d, 1H), 8.46 (s, 1H).

Example 9 ethyl3-(3-chloro-5-fluorobenzyl)-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 1. The reaction time was 1 h. Proceeding from 200 mg (0.58 mmol)of ethyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 2A and 142 mg (0.63 mmol) of1-(bromomethyl)-3-chloro-5-fluorobenzene, 255 mg (90% of theory) of thetitle compound were obtained.

LC-MS (Method 1): R_(t)=0.97 min; m/z=487 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): 8=1.23 (t, 3H), 3.34 (s, 3H), 3.37 (s, 3H),4.19 (q, 2H), 5.03 (s, 2H), 7.19 (d, 1H), 7.22-7.25 (m, 1H), 7.27 (s,1H), 7.28-7.31 (m, 1H), 7.32-7.37 (m, 1H), 7.40 (d, 1H), 8.36 (s, 1H).

Example 10 ethyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[3-fluoro-5-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 1. The reaction time was 1 h. Proceeding from 200 mg (0.58 mmol)of ethyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 2A and 164 mg (0.63 mmol) of1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene, 278 mg (91% oftheory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.01 min; m/z=521 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): 8=1.23 (s, 3H), 3.31 (s, 3H), 3.37 (s, 3H),4.20 (q, 2H), 5.12 (s, 2H), 7.23 (dd, 1H), 7.28 (d, 1H), 7.39 (d, 1H),7.52 (d, 1H), 7.58-7.63 (m, 2H), 8.37 (s, 1H).

Example 11 ethyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate)

Method A: The preparation and purification of the title compound wereanalogous to Example 8. The reaction time was 4 days. Proceeding from300 mg (80% purity, 0.65 mmol) of ethyl2,4-dioxo-3-[4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 21A and 375 mg (1.30 mmol) of1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-benzimidazol-2-onefrom Example 3A, after additional purification by means of flashchromatography (dichloromethane/methanol 98:2), 190 mg (52% of theory)of the title compound were obtained.

LC-MS (Method 5): R_(t)=1.08 min; m/z=529 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 2.35-2.43 (m, 1H),2.44-2.48 (m, 1H), 3.03-3.15 (m, 1H), 3.21-3.29 (m, 1H), 3.31 (s, 3H),3.36 (s, 3H), 4.18 (q, 2H), 6.35-6.58 (m, 1H), 7.13-7.28 (m, 2H), 7.37(t, 2H), 7.45-7.55 (m, 2H), 8.33 (s, 1H).

Method B: In another experiment, in an analogous manner, 1.00 g of thecompound from Example 21A were used. After purification by flashchromatography, however, the product (1.20 g) was only of 63% purity(corresponding to about 50% of theory). This was separated directly bypreparative chiral HPLC (Method 12) into the enantiomers: 377 mg (24% oftheory) of the enantiomer which elutes first (see Example 12) and 331 mg(21% of theory) of the enantiomer which elutes later (see Example 13)were obtained.

Example 12 ethyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[(1S)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(S enantiomer)

Method A: Enantiomer which elutes first (377 mg) from the separation ofthe compound from Example 11 (Method B) by preparative HPLC on a chiralphase (Method 12).

Chiral HPLC (Method 13): R_(t)=9.39 min, 100% ee.

Specific optical rotation: α_(D) ²⁰=−117.1° (acetonitrile, c=0.05 g/100ml).

Method B: Under an argon atmosphere, 5.68 g (16.49 mmol) of the compoundfrom Example 2A, 4.00 g (19.79 mmol) of(1R)-4-(trifluoromethyl)indan-1-ol from Example 15A and 7.78 g (29.68mmol) of triphenylphosphine were initially charged in 200 ml of DMF and100 ml of THF and cooled to 0° C. 5.19 ml (5.33 g, 26.4 mmol) ofdiisopropyl azodicarboxylate were added dropwise. The cooling bath wasremoved and the mixture was stirred at RT for 2 h. Subsequently, 25 mlof 1N hydrochloric acid were added and the mixture was stirred for 15min. For workup, about 2 l of ethyl acetate and 1.33 l of dilutehydrochloric acid (about 2.5N) were added. After stirring, the organicphase was separated, washed twice with dilute hydrochloric acid, oncewith a 1N sodium carbonate solution and once with a saturated sodiumchloride solution and dried over sodium sulphate. The solvents wereremoved on a rotary evaporator. The residue was purified by preparativeHPLC (Method 11). This gave 5.15 g of the title compound (59% oftheory).

LC-MS (Method 1): R_(t)=1.04 min; m/z=529 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.31 (t, 3H), 2.36-2.51 (m, 1H), 2.59(ddt, 1H), 3.07-3.20 (m, 1H), 3.39 (s, 3H), 3.40 (s, 3H), 3.42-3.54 (m,1H), 4.29 (q, 2H), 6.57-6.68 (br. m, 1H), 6.94 (br.s, 1H), 7.02 (s, 2H),7.25-7.38 (m, 2H), 7.49 (d, 1H), 8.31 (s, 1H).

Chiral HPLC (Method 13): R_(t)=9.39 min, 92% ee.

Example 13 ethyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(R enantiomer)

Method A: Enantiomer which elutes last (331 mg) from the separation ofthe compound from Example 11 (Method B) by preparative HPLC on a chiralphase (Method 12).

Chiral HPLC (Method 13): R_(t)=11.12 min, 92% ee.

Method B: 3.05 g (8.86 mmol) of ethyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 2A, 2.15 g (10.63 mmol) of(1S)-4-(trifluoromethyl)indan-1-ol from Example 14A and 6.97 g (26.6mmol) of triphenylphosphine were initially charged under argon inTHF/DMF 1:1 (1.7 l) and cooled to −15° C. 3.48 ml (17.71 mmol) ofdiisopropyl azodicarboxylate were added gradually. Subsequently, thereaction mixture was stirred at RT for another 30 min. While coolingwith ice, a further 0.8 equivalent (1.39 ml, 6.86 mmol) of diisopropylazodicarboxylate was added dropwise and the reaction mixture was stirredat RT for 1 h. The reaction mixture was cooled to −40° C., admixed with1M hydrochloric acid, diluted with ethyl acetate and stirred vigorouslyfor a few minutes. The organic phase was separated, washed twice with 1Msodium carbonate solution and once with saturated sodium chloridesolution, dried over sodium sulphate and concentrated on a rotaryevaporator. The residue was admixed with MTBE and stirred at RTovernight, then stirred with ice bath cooling for 20 min. Theprecipitated solid was filtered off with suction and washed with coldMTBE. The whole filtrate was concentrated and purified by means ofpreparative HPLC (Method 7). This gave 2.90 g (62% of theory) of thetitle compound.

LC-MS (Method 1): R_(t)=1.05 min; m/z=529 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ=1.36 (t, 3H), 2.42-2.55 (m, 1H), 2.57-2.71(m, 1H), 3.12-3.24 (m, 1H), 3.43 (s, 3H), 3.43-3.58 (m, 1H), 3.45 (s,3H), 4.33 (q, 2H), 6.60-6.73 (m, 1H), 6.99 (s, 1H), 7.07 (s, 2H),7.30-7.42 (m, 2H), 7.54 (d, 2H), 8.36 (s, 1H).

Example 14 ethyl1-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)-benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 1. The reaction time was 1 h. Proceeding from 500 mg (1.51 mmol)of ethyl1-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 36A and 421 mg (1.67 mmol) of2-methyl-3-(trifluoromethyl)benzyl bromide, 606 mg (purity approx. 83%,66% of theory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.96 min; m/z=503 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 2.46 (s, 3H), 3.30 (s,partly concealed by water signal), 4.19 (q, 2H), 5.07 (s, 2H), 7.18-7.23(m, 3H), 7.31-7.42 (m, 2H), 7.57-7.62 (m, 1H), 8.39 (s, 1H), 11.13 (s,1H).

Example 15 ethyl3-(2,3-dichlorobenzyl)-1-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetradropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 1. The reaction time was 5 h. Proceeding from 200 mg (0.61 mmol)of ethyl1-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 36A and 130 mg (0.67 mmol) of 2,3-dichlorobenzyl chloride,after additional purification by means of preparative HPLC (Method 8),40 mg (13% of theory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.94 min; m/z=489 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 3.30 (s, partlyconcealed by water signal), 4.19 (q, 2H), 5.09 (s, 2H), 7.16-7.27 (m,4H), 7.32 (t, 1H), 7.56-7.60 (m, 1H), 8.41 (s, 1H), 11.14 (s, 1H).

Example 16 ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 1. The reaction time was 5 h. Proceeding from 200 mg (0.61 mmol)of ethyl1-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 36A and 182 mg (0.67 mmol) of2-chloro-3-(trifluoromethyl)benzyl bromide, after purification by meansof preparative HPLC (Method 8), 33 mg (10% of theory) of the titlecompound were obtained.

LC-MS (Method 1): R_(t)=0.97 min; m/z=523 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 3.30 (s, partlyconcealed by water signal), 4.20 (q, 2H), 5.14 (s, 2H), 7.19-7.23 (m,3H), 7.48-7.55 (m, 1H), 7.58-7.62 (m, 1H), 7.78-7.82 (m, 1H), 8.42 (s,1H), 11.14 (s, 1H).

Example 17 ethyl3-[3-chloro-2-(trifluoromethyl)benzyl]-1-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

To a solution of 0.74 g (2.24 mmol) of ethyl1-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 36A in 28 ml of DMF were added 1.04 g (65% purity, 2.46mmol) of 1-(bromomethyl)-3-chloro-2-(trifluoromethyl)benzene(preparation: see WO 2004/52858, page 149, Example 176), 0.62 g (4.48mmol) of potassium carbonate and 0.04 g (0.22 mmol) of potassium iodide,and the mixture was stirred at 60° C. for 5 h. For workup, the reactionmixture was admixed with water and extracted three times with ethylacetate. The combined organic phases were washed with saturated sodiumchloride solution, dried over magnesium sulphate, filtered andconcentrated. The residue was purified by means of flash silica gelchromatography (dichloromethane/methanol, 50:1). This gave 0.36 g (29%of theory) of the title compound.

LC-MS (Method 1): R_(t)=0.96 min; MS (ESIpos): m/z=523 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 3.3 (s, concealed byDMSO signal), 4.19 (q, 2H), 5.18-5.24 (m, 2H), 7.16-7.23 (m, 3H),7.33-7.38 (m, 1H), 7.55-7.67 (m, 2H), 8.43 (s, 1H), 11.15 (s, 1H).

Example 18 ethyl3-[3-chloro-2-(trifluoromethyl)benzyl]-1-(3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

120 mg (0.23 mmol) of ethyl3-[3-chloro-2-(trifluoromethyl)benzyl]-1-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 17 were initially charged in DMF (3 ml), and 39 mg (0.25mmol) of iodoethane, 63 mg (0.46 mmol) of potassium carbonate and 4 mg(0.02 mmol) of potassium iodide were added. The reaction mixture wasleft to stir at 60° C. for 5 h. The reaction mixture cooled to RT wasadmixed with water, and the precipitate was filtered off with suction,washed with water and MTBE, and dried under reduced pressure at 50° C.After additional purification by means of flash chromatography(dichloromethane/methanol 70:1), 73 mg (55% of theory) of the titlecompound were obtained.

LC-MS (Method 1): R_(t)=1.11 min; m/z=551 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.19-1.26 (m, 6H), 3.37 (s, 3H), 3.87(q, 2H), 4.20 (q, 2H), 5.20-5.25 (m, 2H), 7.22-7.30 (m, 2H), 7.31-7.35(m, 1H), 7.44-7.46 (m, 1H), 7.57-7.67 (m, 2H), 8.47 (s, 1H).

Example 19 ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 18. Proceeding from 90 mg (0.17 mmol) of ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 16 and 29 mg (0.19 mmol) of iodoethane, 75 mg (77% oftheory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.11 min; m/z=551 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.19-1.27 (m, 6H), 3.37 (s, partlyconcealed by water signal), 3.88 (q, 2H), 4.20 (q, 2H), 5.16 (s, 2H),7.22-7.31 (m, 2H), 7.44-7.48 (m, 1H), 7.50-7.60 (m, 2H), 7.78-7.82 (m,1H), 8.47 (s, 1H).

Example 20 ethyl1-(3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 18. Proceeding from 214 mg (0.42 mmol) of ethyl1-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 14 and 73 mg (0.47 mmol) of iodoethane, 152 mg (65% oftheory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.06 min; m/z=531 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.19-1.26 (m, 6H), 2.46 (s, partlyconcealed by DMSO signal), 3.37 (s, partly concealed by water signal),3.87 (q, 2H), 4.20 (q, 2H), 5.09 (s, 2H), 7.23-7.30 (m, 2H), 7.33-7.39(m, 2H), 7.47-7.49 (m, 1H), 7.59-7.62 (m, 1H), 8.44 (s, 1H).

Example 21 ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 1. The reaction time was 5 h. Proceeding from 200 mg (0.54 mmol)of ethyl1-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 22A and 162 mg (0.59 mmol) of2-chloro-3-(trifluoromethyl)benzyl bromide, 204 mg (66% of theory) ofthe title compound were obtained.

LC-MS (Method 1): R_(t)=1.17 min; m/z=565 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.19-1.26 (m, 9H), 3.84-3.95 (m, 4H),4.20 (q, 2H), 5.16 (s, 2H), 7.22-7.27 (m, 1H), 7.34 (d, 1H), 7.44-7.48(m, 1H), 7.50-7.60 (m, 2H), 7.78-7.83 (m, 1H), 8.48 (s, 1H).

Example 22 ethyl1-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 1. The reaction time was 5 h. Proceeding from 200 mg (0.54 mmol)of ethyl1-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 22A and 150 mg (0.59 mmol) of2-methyl-3-(trifluoromethyl)benzyl bromide, 174 mg (59% of theory) ofthe title compound were obtained.

LC-MS (Method 1): R_(t)=1.16 min; m/z=545 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (d, 9H), 2.46 (s, 3H), 3.83-3.95(m, 4H), 4.20 (q, 2H), 5.09 (s, 2H), 7.22-7.26 (m, 1H), 7.31-7.41 (m,3H), 7.46-7.49 (m, 1H), 7.58-7.62 (m, 1H), 8.46 (s, 1H).

Example 23 ethyl3-(2,3-dichlorobenzyl)-1-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 1. The reaction time was 5 h. Proceeding from 200 mg (0.53 mmol)of ethyl1-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 22A and 115 mg (0.59 mmol) of 2,3-dichlorobenzyl chloride,244 mg (81% of theory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.15 min; m/z=531 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.18-1.27 (m, 9H), 3.82-3.97 (m, 4H),4.20 (q, 2H), 5.11 (s, 2H), 7.19-7.27 (m, 2H), 7.30-7.38 (m, 2H), 7.46(d, 1H), 7.59 (d, 1H), 8.47 (s, 1H).

Example 24 ethyl1-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[3-fluoro-2-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 1. The reaction time was 5 h. Proceeding from 165 mg (0.44 mmol)of ethyl1-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 22A and 125 mg (0.48 mmol) of1-(bromomethyl)-3-fluoro-2-(trifluoromethyl)benzene, 198 mg (82% oftheory) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.28 min; m/z=549 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (td, 9H), 3.82-3.96 (m, 4H),4.20 (q, 2H), 5.21 (s, 2H), 7.17-7.26 (m, 2H), 7.31-7.49 (m, 3H), 7.67(q, 1H), 8.49 (s, 1H).

Example 25 ethyl3-[3-chloro-2-(trifluoromethyl)benzyl]-1-[1-methyl-2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzimidazol-5-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

121 mg (0.23 mmol) of ethyl3-[3-chloro-2-(trifluoromethyl)benzyl]-1-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 17 were initially charged in DMF (3 ml), and 76 μl (130 mg,0.46 mmol) of 2,2,2-trifluoroethyl trichloromethanesulphonate, 64 mg(0.46 mmol) of potassium carbonate and 4 mg (0.02 mmol) of potassiumiodide were added. The reaction mixture was left to stir at 60° C. for 5h. The reaction mixture cooled to RT was admixed with water, and theprecipitate was filtered off with suction, washed with water and MTBE,and dried under reduced pressure at 50° C. After additional purificationby means of flash chromatography (dichloromethane/methanol 70:1), 91 mg(63% of theory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.16 min; m/z=605 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 3.41 (s, 3H), 4.20 (q,2H), 4.80 (q, 2H), 5.22 (br.s, 2H), 7.31-7.39 (m, 3H), 7.53 (s, 1H),7.57-7.67 (m, 2H), 8.44 (s, 1H).

Example 26 ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-[1-methyl-2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzimidazol-5-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 25. Proceeding from 89 mg (0.17 mmol) of ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 16 and 96 mg (0.34 mmol) of 2,2,2-trifluoroethyltrichloromethanesulphonate, 80 mg (75% of theory) of the title compoundwere obtained.

LC-MS (Method 1): R_(t)=1.16 min; m/z=605 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 3.41 (s, 3H), 4.21 (q,2H), 4.80 (q, 2H), 5.15 (s, 2H), 7.31-7.39 (m, 2H), 7.50-7.56 (m, 2H),7.57-7.61 (m, 1H), 7.78-7.82 (m, 1H), 8.43 (s, 1H).

Example 27 ethyl1-[1-methyl-2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzimidazol-5-yl]-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 25. Proceeding from 133 mg (purity 75%, 0.19 mmol) of ethyl1-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 14 and 111 mg (0.39 mmol) of 2,2,2-trifluoroethyltrichloromethanesulphonate, after purification by means of flashchromatography (dichloromethane/methanol 100:1), 41 mg (35% of theory)of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.15 min; m/z=585 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 2.46 (s, 3H), 3.41 (s,3H), 4.20 (q, 2H), 4.79 (q, 2H), 5.08 (s, 2H), 7.32-7.41 (m, 4H),7.54-7.57 (m, 1H), 7.58-7.63 (m, 1H), 8.41 (s, 1H).

Example 28 ethyl1-[1-methyl-2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzimidazol-5-yl]-2,4-dioxo-3-[(1R)-4-(tri-fluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(R enantiomer)

400 mg (0.97 mmol) of ethyl1-[1-methyl-2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzimidazol-5-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 25A, 235 mg (1.16 mmol) of(1S)-4-(trifluoromethyl)indan-1-ol from Example 14A and 763 mg (2.91mmol) of triphenylphosphine were initially charged under argon inDMF/THF 1:1 (19.6 ml), and the reaction mixture was cooled to −15° C.and admixed with 0.53 ml (2.71 mmol) of diisopropyl azodicarboxylate.The reaction mixture was left to stir at RT for 30 min, then, whilecooling with ice, a further 0.2 equivalent (38 μl, 0.19 mmol) ofdiisopropyl azodicarboxylate was added dropwise and the mixture wasstirred at RT for 1 h. The reaction mixture was cooled to 0° C., admixedwith 1 N hydrochloric acid and stirred at RT for 15 min. The solutionformed was extracted with ethyl acetate. The organic phase wassuccessively washed twice with 1 N hydrochloric acid, twice withsaturated sodium carbonate solution and once with saturated sodiumchloride solution, dried over magnesium sulphate and concentrated. Theresidue was purified by preparative HPLC (Method 7). This gave 370 mg(57% of theory) of the title compound.

LC-MS (Method 5) R_(t)=1.17 min; m/z=597 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.23 (t, 3H), 2.29-2.42 (m, 1H),2.43-2.57 (m, 1H), 3.00-3.12 (m, 1H), 3.31-3.44 (m, 4H), 4.20 (q, 2H),4.41 (q, 2H), 6.47-6.60 (m, 1H), 6.94-7.07 (m, 3H), 7.17-7.28 (m, 2H),7.41 (d, 1H), 8.22 (s, 1H).

Example 29 ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-[3-(cyclopropylmethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

To a solution of 90 mg (0.17 mmol) of ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 16 in DMF (2 ml) were added 254 mg (0.18 mmol) of(bromomethyl)cyclopropane, 47 mg of potassium carbonate and 3 mg ofpotassium iodide. Subsequently, the reaction mixture was left to stir at60° C. for 5 h. After cooling to RT, water was added and the precipitateformed was filtered off. The solid was washed successively with waterand MTBE, and dried under reduced pressure at 50° C. The solid wasdissolved in dichloromethane and purified by means of flashchromatography (dichloromethane/methanol 70/1). The resulting productwas dried under high vacuum. This gave 67 mg (66% of theory) of thetitle compound.

LC-MS (Method 1): R_(t)=1.17 min; m/z=577 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ=0.34-0.50 (m, 4H), 1.14-1.26 (m, 4H), 3.38(s, 3H), 3.72 (d, 2H), 4.20 (q, 2H), 5.15 (s, 2H), 7.23-7.31 (m, 2H),7.50-7.60 (m, 3H), 7.80 (d, 1H), 8.46 (s, 1H).

Example 30 ethyl1-[3-(cyclopropylmethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]-3-[2-methyl-3-(tri-fluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 29. Proceeding from 133 mg (75% purity, 0.19 mmol) of ethyl1-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 14 and 29 mg (0.18 mmol) of (bromomethyl)cyclopropane, 69mg (56% of theory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.16 min; m/z=557 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=0.35-0.41 (m, 2H), 0.42-0.49 (m, 2H),1.16-1.26 (m, 4H), 2.46 (s, 3H), 3.38 (s, 3H), 3.72 (d, 2H), 4.20 (q,2H), 5.09 (s, 2H), 7.23-7.30 (m, 2H), 7.33-7.40 (m, 2H), 7.52-7.54 (m,1H), 7.59-7.62 (m, 1H), 8.44 (s, 1H).

Example 31 ethyl3-[3-chloro-2-(trifluoromethyl)benzyl]-1-[3-(cyclopropylmethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 29. Proceeding from 120 mg (0.23 mmol) of ethyl3-[3-chloro-2-(trifluoromethyl)benzyl]-1-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 17 and 34 mg (0.25 mmol) of (bromomethyl)cyclopropane, 89mg (62% of theory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.17 min; m/z=577 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=0.35-0.41 (m, 2H), 0.41-0.49 (m, 2H),1.14-1.27 (m, 4H), 3.38 (s, 3H), 3.72 (d, 2H), 4.20 (q, 2H), 5.22 (br.s,2H), 7.22-7.30 (m, 2H), 7.31-7.36 (m, 1H), 7.49-7.52 (m, 1H), 7.57-7.67(m, 2H), 8.47 (s, 1H).

Example 32 ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-[1-methyl-3-(oxetan-2-ylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate)

100 mg (0.23 mmol) of ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 16 were initially charged in 2.4 ml of DMF, and 32 mg (0.21mmol) of 2-(bromomethyl)oxetane, 53 mg (0.38 mmol) of potassiumcarbonate and 3 mg (0.02 mmol) of potassium iodide were added. Thereaction mixture was stirred at 60° C. for 2 h. Subsequently, another 1equivalent of 2-(bromomethyl)oxetane was added at RT and the reactionmixture was stirred at 80° C. for 2 h. For workup, the reaction mixturewas admixed with water, and the precipitate was filtered off withsuction, washed with water and dried under reduced pressure at 50° C.The solid was dissolved in dichloromethane and purified by means offlash silica gel chromatography (dichloro-methane/methanol 70:1). Thisgave 56 mg (50% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.09 min; m/z=593 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): 8=1.23 (t, 3H), 2.10-2.22 (m, 1H), 2.25-2.38(m, 1H), 3.36 (s, 3H), 3.39-3.48 (m, 1H), 3.73 (q, 1H), 3.85-3.92 (m,1H), 3.92-3.98 (m, 1H), 4.11-4.17 (m, 1H), 4.21 (q, 2H), 5.15 (s, 2H),7.25-7.33 (m, 2H), 7.45 (s, 1H), 7.53 (t, 1H), 7.60 (d, 1H), 7.80 (d,1H), 8.46 (s, 1H).

Example 33 ethyl1-(3-cyclobutyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)-benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

39 μl (0.49 mmol) of cyclobutanol and 130 mg (0.49 mmol) oftriphenylphosphine were initially charged under argon in THF (2.5 ml),98 μl (0.49 mmol) of diisopropyl azodicarboxylate were slowly addeddropwise and then 100 mg (0.19 mmol) of ethyl1-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 14 were added. The reaction mixture was stirred at RT for16 h. The mixture was concentrated and purified by means of preparativeHPLC (Method 8). This gave 46 mg (41% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.16 min; m/z=557 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 1.72-1.91 (m, 2H),2.20-2.30 (m, 2H), 2.47 (s, partly concealed by DMSO signal), 2.75-2.87(m, 2H), 3.31 (s, partly concealed by water signal), 4.20 (q, 2H),4.78-4.88 (m, 1H), 5.09 (s, 2H), 7.24-7.29 (m, 2H), 7.33-7.42 (m, 2H),7.60 (d, 1H), 7.67 (s, 1H), 8.45 (s, 1H).

Example 34 ethyl1-(3-isopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)-benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 33. Proceeding from 100 mg (0.19 mmol) of ethyl1-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)-benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 14 and 38 μl (0.49 mmol) of 2-propanol, after additionalpurification by means of preparative HPLC (Method 8), 38 mg (34% oftheory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.12 min; m/z=545 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 1.45 (d, 6H), 2.46 (s,partly concealed by DMSO signal), 3.31 (s, partly concealed by watersignal), 4.20 (q, 2H), 4.54-4.65 (m, 1H), 5.09 (s, 2H), 7.22-7.29 (m,2H), 7.32-7.41 (m, 2H), 7.58-7.62 (m, 2H), 8.43 (s, 1H).

Example 35 ethyl1-(3-cyclopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)-benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

250 mg (0.49 mmol) of ethyl1-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 14, 85 mg (0.99 mmol) of cyclopropylboronic acid and 0.41ml (2.98 mmol) of triethylamine were initially charged indichloro-methane (4 ml). Molecular sieve (3 Å) and 271 mg (1.49 mmol) ofcopper(II) acetate were added and the reaction mixture was stirred at RTfor 3 days. The mixture was diluted with ethyl acetate, washed twicewith 1M hydrochloric acid, once with saturated sodium hydrogencarbonatesolution and once with saturated sodium chloride solution. The organicphase was dried over magnesium sulphate, filtered and concentrated. Theresidue was purified by means of preparative HPLC (Method 8). This gave155 mg (56% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.06 min; m/z=543 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=0.86-0.92 (m, 2H), 0.99-1.06 (m, 2H),1.23 (t, 3H), 2.46 (s, partly concealed by DMSO signal), 2.87-2.95 (m,1H), 3.31 (s, partly concealed by water signal), 4.20 (q, 2H), 5.08 (s,2H), 7.22-7.28 (m, 2H), 7.32-7.43 (m, 2H), 7.47 (s, 1H), 7.60 (d, 1H),8.41 (s, 1H).

Example 36 ethyl1-(3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)-benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

To a solution of 250 mg (0.76 mmol) of ethyl1-(3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 34A in 10 ml of DMF were added 211 mg (0.83 mmol) of1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene, 209 mg (1.51 mmol)of potassium carbonate and 13 mg (0.08 mmol) of potassium iodide, andthe mixture was stirred at 60° C. for 3 h. For workup, the reactionmixture was admixed with water, and the precipitate formed was filteredoff with suction, washed with water and MTBE, and dried under highvacuum at 50° C. overnight. This gave 42 mg (11% of theory) of thetarget compound.

LC-MS (Method 3): R_(t)=1.19 min; MS (ESIpos): m/z=503 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 3.41 (s, 3H), 4.17 (q,2H), 5.20 (s, 2H), 7.07-7.16 (m, 3H), 7.29-7.36 (m, 1H), 7.46 (s, 1H),7.62 (d, 1H), 8.28 (s, 1H), 11.70 (s, 1H).

Example 37 ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate

200 mg (0.63 mmol) of ethyl2,4-dioxo-1-(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 26A were initially charged in 8 ml of DMF. 190 mg (0.70mmol) of 1-(bromomethyl)-2-chloro-3-(trifluoromethyl)benzene, 175 mg(1.27 mmol) of potassium carbonate and 10.5 mg (63 μmol) of potassiumiodide were added and the reaction mixture was stirred at 60° C. for 5h. After cooling to RT, water was added to the mixture. The precipitatewas filtered off, washed with a little water and MTBE, and dried in adrying cabinet at 50° C. The resulting product was dissolved in a littleDMF and purified by means of preparative HPLC (Method 8). This gave 111mg (35% of theory) of the title compound.

LC-MS (Method 3): R_(t)=1.13 min; m/z=509 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 4.20 (q, 2H), 5.14 (s,2H), 7.02 (d, 1H), 7.09 (dd, 1H), 7.15 (s, 1H), 7.51 (t, 1H), 7.59 (d,1H), 7.79 (d, 1H), 8.41 (s, 1H), 10.88 (d, 2H).

Example 38 ethyl1-[3-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzimidazol-5-yl]-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 25. Proceeding from 91 mg (0.18 mmol) of ethyl1-(3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 36 and 101 mg (0.36 mmol) of 2,2,2-trifluoroethyltrichloromethanesulphonate, 57 mg (52% of theory) of the title compoundwere obtained.

LC-MS (Method 1): R_(t)=1.11 min; m/z=585 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 2.46 (s, 3H), 3.38 (s,3H), 4.19 (q, 2H), 4.86 (q, 2H), 5.09 (s, 2H), 7.28-7.41 (m, 3H), 7.44(d, 1H), 7.50 (d, 1H), 7.61 (d, 1H), 8.47 (s, 1H).

Example 39 ethyl1-[1-(cyclopropylmethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

91 mg (0.18 mmol) of ethyl1-(3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 36 were reacted analogously to Example 29 with 26 mg (0.19mmol) of (bromomethyl)cyclopropane. After 2 h of reaction time, anadditional 24 mg (0.17 mmol) of (bromomethyl)cyclopropane were added andthe reaction mixture was stirred at 80° C. for another 1 h. The productwas precipitated by addition of water and filtered off. After additionalpurification by means of flash chromatography (dichloromethane/methanol70:1), 51 mg (51% of theory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.13 min; m/z=557 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): 8=0.36-0.42 (m, 2H), 0.42-0.50 (m, 2H),1.14-1.20 (m, 1H), 1.23 (t, 3H), 2.46 (s, 3H), 3.35 (s, 3H), 3.77 (d,2H), 4.19 (q, 2H), 5.09 (s, 2H), 7.24 (dd, 1H), 7.32-7.44 (m, 4H),7.58-7.62 (m, 1H), 8.45 (s, 1H).

Example 40 ethyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 1, with reaction time 2 h. Proceeding from 200 mg (0.60 mmol) ofethyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 28A and 168 mg (0.66 mmol) of1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene, 288 mg (93% oftheory) of the title compound were obtained.

LC-MS (Method 5): R_(t)=1.10 min; m/z=504 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 2.46 (s, 3H), 3.38 (s,3H), 4.20 (q, 2H), 5.07 (s, 2H), 7.31-7.42 (m, 3H), 7.43-7.48 (m, 1H),7.58-7.62 (m, 1H), 7.63-7.66 (m, 1H), 8.44 (s, 1H).

Example 41 ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 1. The reaction time was 2 h. Proceeding from 200 mg (0.60 mmol)of ethyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 28A and 181 mg (0.66 mmol) of1-(bromomethyl)-2-chloro-3-(trifluoromethyl)benzene, 263 mg (79% oftheory) of the title compound were obtained.

LC-MS (Method 5): R_(t)=1.11 min; m/z=523 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ=1.23 (t, 3H), 3.38 (s, 3H), 4.20 (q, 2H),5.14 (s, 2H), 7.38-7.48 (m, 2H), 7.53 (t, 1H), 7.59 (d, 1H), 7.64 (s,1H), 7.80 (d, 1H), 8.47 (s, 1H).

Example 42 ethyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(R enantiomer)

Method A: A solution of 200 mg (0.60 mmol) of ethyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 28A and 475 mg (1.81 mmol) of triphenylphosphine in THF/DMF1:1 (7.6 ml) under argon was cooled to −30° C. 238 μl (1.20 mmol) ofdiisopropyl azodicarboxylate were added dropwise and then a solution of146 mg (0.69 mmol) of (1S)-4-(trifluoromethyl)indan-1-ol from Example14A in about 1 ml of THF was added dropwise. The reaction mixture waswarmed to RT and stirred at RT for 30 min. For workup, the mixture wascooled to 0° C., admixed with 5 ml of 1M hydrochloric acid, warmed to RTand stirred for 30 min. The mixture was then extracted with ethylacetate. The organic phase was washed twice with 1M hydrochloric acidand once with saturated sodium chloride solution, dried over magnesiumsulphate and concentrated under reduced pressure. The residue wassubjected to extractive stirring with ethanol, and the precipitatedsolid was filtered off with suction and discarded. The filtrate wasconcentrated, dissolved in a little dichloromethane and purified bymeans of flash chromatography (dichloromethane/methanol 120:1→20:1).This gave 135 mg (43% of theory) of the title compound in about 95%purity.

LC-MS (Method 1): R_(t)=1.13 min; m/z=516 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 2.37-2.43 (m, 1H),2.43-2.48 (m, 1H, partly concealed by DMSO signal), 3.03-3.14 (m, 1H),3.22-3.30 (m, 1H, partly concealed by water signal), 3.38 (s, 3H), 4.18(q, 2H), 6.34-6.56 (m, 1H), 7.32-7.43 (m, 3H), 7.45-7.50 (m, 1H), 7.53(d, 1H), 7.55-7.64 (m, 1H), 8.35 (s, 1H).

In an analogous experiment, it was possible to isolate a fraction with99% purity. For this batch, the specific optical rotation measured was:

Specific optical rotation: α_(D) ²⁰=+132.9°, (chloroform, c=0.395 g/100ml).

Method B: A solution of 5.0 g (15.1 mmol) of ethyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example, 6.73 g (25.7 mmol) of triphenylphosphine and 3.66 g (18.1mmol) of (1S)-4-(trifluoromethyl)indan-1-ol from Example 14A wasinitially charged under argon in 240 ml of DMF/THF 2:1 (v/v) and cooledto −15° C. 4.76 ml (24.15 mmol) of diisopropyl azodicarboxylate wasslowly added dropwise at such a rate that the temperature of thereaction mixture did not rise above −10° C. At the end of the addition,the mixture was stirred at −10° C. for another 1 h, then warmed to RTand poured onto 1.3 l of water. The mixture was extracted twice with 300ml each time of ethyl acetate. The combined organic phases were washedwith a saturated sodium chloride solution, dried over magnesium sulphateand freed of the solvent on a rotary evaporator. The residue (18 g) waspurified in two chromatography steps: first using a 200 g silica gelcolumn with dichloromethane/acetone 97.5:2.5 as the eluent. Theresulting product-containing fractions were concentrated and the residuewas applied again to a 200 g silica gel column. 2.5 l ofcyclohexane/ethyl acetate 1:1 as eluent were used to elute furtherimpurities, then the desired product was eluted from the column withdichloromethane/methanol 95:5. This gave 3.40 g (44% of theory) of thetitle compound in 95% purity (NMR showed about 5% ethyl acetate). Afurther 920 mg were obtainable by a new purification of a mixedfraction. Overall yield: 4.32 g (56% of theory).

LC-MS (Method 1): R_(t)=1.15 min; m/z=516 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.31 (t, 3H), 2.37-2.49 (m, 1H), 2.59(dtd, 1H), 3.14 (dt, 1H), 3.40 (s, 3H), 3.42-3.53 (m, 1H), 4.29 (q, 2H),6.54-6.68 (m, 1H), 7.06 (d, 1H), 7.17 (d, 1H), 7.22 (s, 1H), 7.26-7.36(m, 2H), 7.49 (d, 1H), 8.28 (s, 1H).

Example 43 ethyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-3-[(1S)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(S enantiomer)

1.00 g (3.02 mmol) of the compound from Example 28A, 732 mg (3.62 mmol)of the compound from Example 15A and 1.35 g (5.13 mmol) oftriphenylphosphine were initially charged in 9 ml of THF and 18 ml ofDMF, and 951 μl (4.83 mmol) of diisopropyl azodicarboxylate were addeddropwise at RT. The reaction mixture was stirred at RT for 1 h. Forworkup, 5 ml of 1N hydrochloric acid were added to the reaction mixturewhile cooling with ice and the mixture was stirred for 10 min. Themixture was then extracted with ethyl acetate. The combined organicphases were washed twice with 1N hydrochloric acid, twice with a 1Msodium carbonate solution and once with a saturated sodium chloridesolution, dried over magnesium sulphate and concentrated on a rotaryevaporator. The residue was purified by preparative HPLC (Method 15).This gave 590 mg (38% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.08 min; m/z=516 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.31 (t, 3H), 2.33-2.50 (m, 1H),2.51-2.67 (m, 1H), 3.14 (dt, 1H), 3.39-3.52 (m, 1H), 3.40 (s, 3H), 4.29(q, 2H), 6.55-6.68 (m, 1H), 7.06 (d, 1H), 7.18 (d, 1H), 7.22 (s, 1H),7.26-7.35 (m, 2H), 7.49 (d, 1H), 8.28 (s, 1H).

Chiral analytical HPLC (Method 27): R_(t)=9.94 min; about 93% ee

Example 44 ethyl1-(3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 1. The reaction time was 5 h. Proceeding from 200 mg (0.58 mmol)of ethyl1-(3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 30A and 161 mg (0.64 mmol) of2-methyl-3-(trifluoromethyl)benzyl bromide, 192 mg (64% of theory) ofthe title compound were obtained.

LC-MS (Method 1): R_(t)=1.11 min; m/z=518 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 1.28 (t, 3H), 2.46 (s,3H), 3.90 (q, 2H), 4.20 (q, 2H), 5.08 (s, 2H), 7.31-7.42 (m, 2H),7.43-7.50 (m, 2H), 7.58-7.62 (m, 1H), 7.64-7.67 (m, 1H), 8.45 (s, 1H).

Example 45 ethyl3-(2,3-dichlorobenzyl)-1-(3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 1. The reaction time was 5 h. Proceeding from 200 mg (0.58 mmol)of ethyl1-(3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 30A and 124 mg (0.64 mmol) of1,2-dichloro-3-(chloromethyl)benzene, 220 mg (75% of theory) of thetitle compound were obtained.

LC-MS (Method 1): R_(t)=1.09 min; m/z=504 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 1.28 (t, 3H), 3.90 (q,2H), 4.20 (q, 2H), 5.10 (s, 2H), 7.21-7.25 (m, 1H), 7.30-7.36 (m, 1H),7.41-7.50 (m, 2H), 7.56-7.60 (m, 1H), 7.63-7.66 (m, 1H), 8.47 (s, 1H).

Example 46 ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 37. Proceeding from 200 mg (0.58 mmol) of ethyl1-(3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 30A and 174 mg (0.63 mmol) of1-(bromomethyl)-2-chloro-3-(trifluoromethyl)benzene, 209 mg (67% oftheory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.11 min; m/z=538 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 1.28 (t, 3H), 3.90 (q,2H), 4.20 (q, 2H), 5.14 (s, 2H), 7.42-7.56 (m, 3H), 7.59 (d, 1H), 7.65(d, 1H), 7.81 (d, 1H), 8.48 (s, 1H).

Example 47 ethyl1-(3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-3-[3-fluoro-2-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 37. Proceeding from 200 mg (0.58 mmol) of ethyl1-(3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 30A and 163 mg (0.63 mmol) of1-(bromomethyl)-3-fluoro-2-(trifluoromethyl)benzene, 159 mg (52% oftheory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.06 min; m/z=522 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 1.28 (t, 3H), 3.90 (q,2H), 4.20 (q, 2H), 5.19 (s, 2H), 7.18-7.23 (m, 1H), 7.37-7.51 (m, 3H),7.62-7.70 (m, 2H), 8.49 (s, 1H).

Example 48 ethyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-3-[2-methyl-3-(trifluoromethyl)-benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 37. Proceeding from 500 mg (1.44 mmol) of ethyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 31A and 400 mg (1.58 mmol) of1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene, 392 mg (50% oftheory) of the title compound were obtained.

LC-MS (Method 3): R_(t)=1.11 min; m/z=520 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 2.46 (s, partlyconcealed by DMSO signal), 3.45 (s, 3H), 4.20 (q, 2H), 5.08 (s, 2H),7.31-7.42 (m, 2H), 7.46 (d, 1H), 7.56-7.63 (m, 2H), 7.88-7.91 (m, 1H),8.48 (s, 1H).

Example 49 ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 37. Proceeding from 184 mg (0.53 mmol) of ethyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 31A and 159 mg (0.58 mmol) of1-(bromomethyl)-2-chloro-3-(trifluoromethyl)benzene, 216 mg (75% oftheory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.11 min; m/z=540 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.24 (t, 3H), 3.45 (s, 3H), 4.20 (q,2H), 5.15 (s, 2H), 7.46 (d, 1H), 7.49-7.55 (m, 1H), 7.56-7.61 (m, 2H),7.78-7.82 (m, 1H), 7.88-7.90 (m, 1H), 8.51 (s, 1H).

Example 50 ethyl3-[3-fluoro-2-(trifluoromethyl)benzyl]-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 37. Proceeding from 200 mg (0.53 mmol) of ethyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 31A and 149 mg (0.58 mmol) of1-(bromomethyl)-3-fluoro-2-(trifluoromethyl)benzene, 241 mg (87% oftheory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.06 min; m/z=524 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 3.45 (s, 3H), 4.20 (q,2H), 5.19 (s, 2H), 7.21 (d, 1H), 7.41 (t, 1H), 7.47 (d, 1H), 7.57 (dd,1H), 7.66 (q, 1H), 7.88 (d, 1H), 8.52 (s, 1H).

Example 51 ethyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(R enantiomer)

8.00 g (23.03 mmol) of ethyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 31A, 5.12 g (25.33 mmol) of(1S)-4-(trifluoromethyl)indan-1-ol from Example 14A and 10.27 g (39.15mmol) of triphenylphosphine were initially charged in 317 ml of THF and317 ml of DMF and cooled to 5° C. 7.25 ml (36.85 mmol) of diisopropylazodicarboxylate were added in portions. The cooling bath was removedand the mixture was stirred at RT for 1 h. For workup, 200 ml of 1Nhydrochloric acid were added and the mixture was stirred vigorously for5 min. 400 ml of ethyl acetate were added. After stirring vigorously for10 minutes, the organic phase was removed. The aqueous phase wasextracted once more with 400 ml of ethyl acetate. The combined organicphases were washed twice with 100 ml each time of a saturated sodiumcarbonate solution, then with 100 ml of a saturated sodium chloridesolution, then dried over sodium sulphate and concentrated on a rotaryevaporator. The residue was admixed with 400 ml of MTBE and stirredwhile cooling with an ice bath for 30 min. The precipitated solid wasfiltered off with suction and washed twice with cold MTBE. The combinedfiltrates were concentrated and the residue was purified by means offlash chromatography (cyclohexane/ethyl acetate 1:2→4 1:4). The productthus obtained was recrystallized from acetonitrile and dried under highvacuum. This gave 6.3 g (50% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.18 min; m/z=532 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.31 (t, 3H), 2.37-2.49 (m, 1H),2.53-2.65 (m, 1H), 3.08-3.20 (m, 1H), 3.40-3.52 (m, 1H), 3.45 (s, 3H),4.29 (q, 2H), 6.56-6.68 (m, 1H), 7.09-7.18 (m, 1H), 7.25-7.36 (m, 3H),7.44 (s, 1H), 7.47-7.54 (m, 1H), 8.29 (s, 1H).

Example 52 ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 37. Proceeding from 200 mg (0.56 mmol) of ethyl2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 59A and 168 mg (0.61 mmol) of1-(bromomethyl)-2-chloro-3-(trifluoromethyl)benzene, 241 mg (77% oftheory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.11 min; m/z=550 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.24 (t, 3H), 1.30 (s, 6H), 3.18 (s,3H), 4.21 (q, 2H), 5.15 (s, 2H), 7.16 (d, 1H), 7.44-7.49 (m, 1H),7.50-7.60 (m, 3H), 7.78-7.83 (m, 1H), 8.44 (s, 1H).

Example 53 ethyl3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 37. Proceeding from 500 mg (1.39 mmol) of ethyl2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 59A and 389 mg (1.53 mmol) of1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene, 571 mg (77% oftheory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.11 min; m/z=530 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.29 (s, 6H), 2.46 (s, 3H), 3.18 (s,3H), 3.30 (s, 3H), 4.20 (q, 2H), 5.08 (s, 2H), 7.15 (d, 1H), 7.34-7.39(m, 2H), 7.44-7.49 (m, 1H), 7.53-7.56 (m, 1H), 7.58-7.63 (m, 1H), 8.42(s, 1H).

Example 54 ethyl3-[3-chloro-2-(trifluoromethyl)benzyl]-2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate

153 mg (0.42 mmol) of ethyl2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 59A were reacted analogously to Example 37 with 198 mg (65%purity, 0.47 mmol) of1-(bromomethyl)-3-chloro-2-(trifluoromethyl)benzene (preparation: see WO2004/52858, page 149, Example 176). For workup, the reaction mixturecooled to RT was admixed with water and extracted twice with ethylacetate. The combined organic phases were washed with saturated sodiumchloride solution, dried over magnesium sulphate and concentrated. Theresidue was stirred with MTBE, and the precipitated solid was filteredoff with suction, washed with MTBE and dried at the high-vacuum pump.This gave 109 mg (46% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.14 min; m/z=550 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 1.29 (s, 6H), 3.18 (s,3H), 4.20 (q, 2H), 5.21 (br.s, 2H), 7.16 (d, 1H), 7.30-7.35 (m, 1H),7.45 (dd, 1H), 7.53 (d, 1H), 7.57-7.66 (m, 2H), 8.45 (s, 1H).

Example 55 ethyl3-[3-fluoro-2-(trifluoromethyl)benzyl]-2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 37. Proceeding from 200 mg (0.56 mmol) of ethyl2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 59A and 158 mg (0.61 mmol) of1-(bromomethyl)-3-fluoro-2-(trifluoromethyl)benzene, 247 mg (80% oftheory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.06 min; m/z=534 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 1.29 (s, 6H), 3.18 (s,3H), 4.20 (q, 2H), 5.20 (s, 2H), 7.13-7.22 (m, 2H), 7.37-7.48 (m, 2H),7.53 (d, 1H), 7.63-7.70 (m, 1H), 8.45 (s, 1H).

Example 56 ethyl3-(2,3-dichlorobenzyl)-2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 37. Proceeding from 200 mg (0.56 mmol) of ethyl2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 59A and 120 mg (0.61 mmol) of1,2-dichloro-3-(chloromethyl)benzene, 230 mg (78% of theory) of thetitle compound were obtained.

LC-MS (Method 1): R_(t)=1.09 min; m/z=520 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 1.29 (s, 6H), 3.18 (s,3H), 4.20 (q, 2H), 7.15 (d, 1H), 7.22 (d, 1H), 7.33 (t, 1H), 7.46 (dd,1H), 7.54 (d, 1H), 7.58 (d, 1H), 8.43 (s, 1H).

Example 57 ethyl2,4-dioxo-3-[4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate)

The preparation and purification of the title compound were analogous toExample 8, with a reaction time of 2 days. Proceeding from 190 mg (0.51mmol) of ethyl2,4-dioxo-3-[4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 21A and 310 mg (1.03 mmol) of1,3,3-trimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-indol-2-onefrom Example 68A, after additional purification by means of flashchromatography (dichloromethane/methanol 98:2), a total of 169 mg (60%of theory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.14 min; m/z=542 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.20-1.25 (m, 3H), 1.29 (s, 6H),2.38-2.43 (m, 1H), 2.44-2.48 (m, 1H, partly concealed by DMSO signal),3.03-3.13 (m, 1H), 3.17 (s, 3H), 3.23-3.29 (m, 1H, partly concealed bywater signal), 4.18 (q, 2H), 6.33-6.56 (m, 1H), 7.13 (d, 1H), 7.32-7.45(m, 2H), 7.45-7.57 (m, 3H), 8.33 (s, 1H).

Example 58 ethyl2,4-dioxo-3-[4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate(R enantiomer)

700 mg (1.96 mmol) of the compound from Example 59A, 515 mg (2.55 mmol)of (S)-4-trifluoromethylindan-1-ol from Example 14A and 1.54 g (5.88mmol) of triphenylphosphine were initially charged in 20 ml of THF and20 ml of DMF at −15° C., and 1.12 ml (5.68 mmol) of diisopropylazodicarboxylate were added dropwise. The reaction mixture was stirredat RT for 2 h. For workup, the mixture was cooled again to −15° C.,admixed with 30 ml of 1N hydrochloric acid, stirred at RT for 10 min andthen extracted with ethyl acetate. The organic phase was washed twicewith 1N hydrochloric acid, once with a 1M sodium carbonate solution andonce with a saturated sodium chloride solution, then dried over sodiumsulphate and concentrated on a rotary evaporator. The residue waspurified by preparative HPLC (Method 7). This gave 725 mg (68% oftheory) of the title compound.

LC-MS (Method 5): R_(t)=1.18 min; m/z=542 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.31 (t, 3H), 1.35 (s., 3H), 1.36 (s.,3H), 2.37-2.50 (m, 1H), 2.58 (dtd, 1H), 3.08-3.18 (m, 1H), 3.20 (s, 3H),3.47 (br.s, 1H), 4.29 (q, 2H), 6.54-6.68 (m, 1H), 6.92 (d, 1H), 7.16(br.s, 1H), 7.21 (d, 1H), 7.26-7.36 (m, 2H), 7.49 (d, 1H), 8.29 (s, 1H).

Example 59 ethyl3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate

125 mg (0.35 mmol) of ethyl2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 64A were initially charged in 3 ml of DMF. 97 mg (0.38mmol) of 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene, 97 mg(0.70 mmol) of potassium carbonate and 6 mg (0.04 mmol) of potassiumiodide were added and the reaction mixture was stirred at 60° C. for 2h. After cooling to RT, water was added to the mixture. The precipitatewas filtered off, washed with a little water and cyclohexane, and driedin a drying cabinet at 50° C. This gave 134 mg (90% purity, 65% oftheory) of the title compound.

LC-MS (Method 1): R_(t)=1.16 min; m/z=530 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.24 (t, 3H), 1.30 (s, 6H), 2.47 (s,3H), 3.14 (s, 3H), 4.20 (q, 2H), 5.09 (s, 2H), 7.22 (dd, 1H), 7.27 (d,1H), 7.31-7.41 (m, 2H), 7.51 (d, 1H), 7.60 (d, 1H), 8.47 (s, 1H).

Example 60 ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 59. Proceeding from 125 mg (0.35 mmol) of ethyl2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 64A and 105 mg (0.38 mmol) of1-(bromomethyl)-2-chloro-3-(trifluoromethyl)benzene, 182 mg (85% oftheory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.16 min; m/z=550 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.24 (t, 3H), 1.31 (s, 6H), 3.15 (s,3H), 4.20 (q, 2H), 5.16 (s, 2H), 7.22 (dd, 1H), 7.26 (d, 1H), 7.50-7.55(m, 2H), 7.58 (d, 1H), 7.80 (d, 1H), 8.49 (s, 1H).

Example 61 ethyl3-[3-chloro-2-(trifluoromethyl)benzyl]-2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate

125 mg (0.35 mmol) of ethyl2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 64A were initially charged in DMF (3 ml). 161 mg (65%purity, 0.38 mmol) of1-(bromomethyl)-3-chloro-2-(trifluoromethyl)benzene, 96 mg (0.70 mmol)of potassium carbonate and 6 mg (0.03 mmol) of potassium iodide wereadded. Subsequently, the reaction mixture was left to stir at 60° C. for2 h. The mixture cooled to RT was admixed with water and extracted twicewith ethyl acetate. The combined organic phases were washed with asaturated sodium chloride solution, dried over magnesium sulphate andconcentrated. The residue was stirred with cyclohexane/ethyl acetate,and the precipitated solid was filtered off with suction and dried underreduced pressure. This gave 133 mg (62% of theory) of the titlecompound.

LC-MS (Method 1): R_(t)=1.16 min; m/z=550 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.24 (t, 3H), 1.30 (s, 6H), 3.15 (s,3H), 4.20 (q, 2H), 5.22 (br.s, 2H), 7.21 (d, 1H), 7.25 (s, 1H), 7.33 (d,1H), 7.51 (d, 1H), 7.56-7.68 (m, 2H), 8.50 (s, 1H).

Example 62 ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(3-hydroxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate)

The preparation and purification of the title compound were analogous toExample 1. The reaction time was 1 h. Proceeding from 105 mg (0.29 mmol)of ethyl1-(3-hydroxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 72A and 88 mg (0.32 mmol) of1-(bromomethyl)-2-chloro-3-(trifluoromethyl)benzene, 133 mg (74% oftheory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.98 min; m/z=552 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 1.41 (s, 3H), 3.14 (s,3H), 4.21 (q, 2H), 5.14 (s, 2H), 6.13 (s, 1H), 7.14 (d, 1H), 7.47-7.57(m, 3H), 7.58-7.62 (m, 1H), 7.78-7.82 (m, 1H), 8.40 (s, 1H).

Example 63 ethyl1-[3-hydroxy-1-methyl-2-oxo-3-(trifluoromethyl)-2,3-dihydro-1H-indol-5-yl]-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate)

The preparation and purification of the title compound were analogous toExample 1. The reaction time was 45 min. Proceeding from 200 mg (0.48mmol) of ethyl1-[3-hydroxy-1-methyl-2-oxo-3-(trifluoromethyl)-2,3-dihydro-1H-indol-5-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 69A and 134 mg (0.53 mmol) of1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene, after additionalpurification by means of HPLC (Method 8), 76 mg (26% of theory) of thetitle compound were obtained.

LC-MS (Method 5): R_(t)=1.11 min; m/z=585 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.24 (t, 3H), 2.46 (s, 3H), 3.22 (s,3H), 4.21 (q, 2H), 5.07 (s, 2H), 7.30 (d, 1H), 7.35 (t, 1H), 7.41 (d,1H), 7.60 (d, 1H), 7.67-7.71 (m, 1H), 7.73 (s, 1H), 7.92 (s, 1H), 8.40(s, 1H).

Example 64 ethyl1-[3-fluoro-1-methyl-2-oxo-3-(trifluoromethyl)-2,3-dihydro-1H-indol-5-yl]-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate

The preparation and purification of the title compound were analogous toExample 1. The reaction time was 45 min. Proceeding from 90 mg (0.21mmol) of ethyl1-[3-fluoro-1-methyl-2-oxo-3-(trifluoromethyl)-2,3-dihydro-1H-indol-5-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 73A and 60 mg (0.23 mmol) of1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene, after additionalpurification by means of HPLC (Method 8), 97 mg (72% of theory) of thetitle compound were obtained.

LC-MS (Method 5): R_(t)=1.24 min; m/z=588 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.24 (t, 3H), 2.46 (s, 3H), 3.27 (s,3H), 4.21 (q, 2H), 5.07 (s, 2H), 7.32-7.37 (m, 1H), 7.38-7.45 (m, 2H),7.60 (d, 1H), 7.84-7.88 (m, 1H), 7.96 (s, 1H), 8.53 (s, 1H).

Example 65 ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1′-methyl-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-5′-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 1. The reaction time was 1 h. Proceeding from 120 mg (0.33 mmol)of ethyl1-(1-methyl-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-5′-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 63A and 101 mg (0.37 mmol) of1-(bromomethyl)-2-chloro-3-(trifluoromethyl)benzene, 177 mg (90% oftheory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.12 min; m/z=548 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 1.55-1.60 (m, 2H),1.64-1.69 (m, 2H), 3.26 (s, 3H), 4.20 (q, 2H), 5.14 (s, 2H), 7.18-7.24(m, 2H), 7.44 (dd, 1H), 7.49-7.58 (m, 2H), 7.78-7.82 (m, 1H), 8.44 (s,1H).

Example 66 ethyl1-(1-methyl-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-5′-yl)-3-[2-methyl-3-(trifluoromethyl)-benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 1. The reaction time was 1.5 h. Proceeding from 120 mg (0.33mmol) of ethyl1-(1-methyl-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-5′-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 63A and 94 mg (0.37 mmol) of1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene, 140 mg (77% oftheory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.12 min; m/z=528 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 1.55-1.60 (m, 2H),1.64-1.69 (m, 2H), 2.46 (s, partly concealed by DMSO signal), 3.26 (s,3H), 4.19 (q, 2H), 5.07 (s, 2H), 7.17-7.25 (m, 2H), 7.32-7.37 (m, 2H),7.44 (dd, 1H), 7.57-7.63 (m, 1H), 8.42 (s, 1H).

Example 67 ethyl1-(1-methyl-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-5′-yl)-2,4-dioxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(R enantiomer)

8.00 g (22.5 mmol) of ethyl1-(1′-methyl-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-5′-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 63A, 5.46 g (27.0 mmol) of(1S)-4-(trifluoromethyl)indan-1-ol (from Example 14A) and 10.0 g (38.26mmol) of triphenylphosphine were initially charged at RT under argon inTHF/DMF 1:1 (215 ml). To this mixture were added dropwise, whilestirring, 7.09 ml (36.02 mmol) of diisopropyl azodicarboxylate. After 1h, an additional 1.2 g (4.51 mmol) of triphenylphosphine and 0.89 ml(4.51 mmol) of diisopropyl azodicarboxylate were added. The reactionmixture was stirred at RT for a further 1.5 h. While cooling with ice,the mixture was admixed with 10 ml 1M hydrochloric acid, stirred for 15min, then extracted with ethyl acetate. The combined organic phases werewashed twice with 1M hydrochloric acid, then twice with a saturatedsodium carbonate solution and once with a saturated sodium chloridesolution, dried over sodium sulphate and concentrated on a rotaryevaporator. The residue was stirred with 100 ml of MTBE and left tostand overnight. The solid formed was filtered off and discarded. Thefiltrate was concentrated on a rotary evaporator. The residue was takenup in a little dichloromethane and purified by means of flashchromatography (eluent: cyclohexane/ethyl acetate 1:2). This gave 7.81 g(59% of theory, 92% purity by NMR) of the title compound.

LC-MS (Method 4): R_(t)=2.49 min; m/z=540 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.31 (t, 3H), 1.54-1.61 (m, 2H),1.69-1.81 (m, 2H), 2.35-2.49 (m, 1H), 2.51-2.66 (m, 1H), 3.05-3.21 (m,1H), 3.28 (s, 3H), 3.39-3.54 (m, 1H), 4.28 (q, 2H), 6.54-6.67 (m, 1H),6.80 (br.s, 1H), 6.97 (d, 1H), 7.19 (d, 1H), 7.24-7.36 (m, 2H), 7.49 (d,1H), 8.26 (s, 1H).

Specific optical rotation: α_(D) ²⁰=+131.7°, (chloroform, c=0.405 g/100ml).

Example 68 ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

To a solution of 629 mg (1.83 mmol) of ethyl1-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 65A in 10 ml of DMF were added 551 mg (2.02 mmol) of1-(bromomethyl)-2-chloro-3-(trifluoromethyl)benzene, 506 mg (3.66 mmol)of potassium carbonate and 30 mg (0.18 mmol) of potassium iodide, andthe mixture was stirred at 60° C. for 1.5 h. For workup, the reactionmixture was admixed with water, and the precipitate formed was filteredoff with suction and washed with water. The crude product thus obtainedwas purified by means of flash silica gel chromatography(dichloromethane/methanol, 98:2). This gave 371 mg (88% purity, 33% oftheory) of the target compound.

LC-MS (Method 1): R_(t)=1.11 min; MS (ESIpos): m/z=536 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (s, 3H), 1.28 (s, 6H), 4.19 (q,2H), 5.13 (s, 2H), 7.04-7.07 (m, 1H), 7.11-7.15 (m, 1H), 7.44-7.47 (m,1H), 7.48-7.54 (m, 1H), 7.59-7.63 (m, 1H), 7.77-7.82 (m, 1H), 8.47 (s,1H), 10.61 (s, 1H).

Example 69 ethyl1-(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-3-[2-chloro-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 1. The reaction time was 2 h. Proceeding from 200 mg (0.53 mmol)of ethyl1-(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 66A and 162 mg (0.59 mmol) of1-(bromomethyl)-2-chloro-3-(trifluoromethyl)benzene, 228 mg (71% oftheory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.18 min; m/z=564 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 1.34 (s, 6H), 2.18 (s,3H), 3.94 (s, 2H), 4.19 (q, 2H), 5.12 (s, 2H), 7.19 (dd, 1H), 7.40 (d,1H), 7.50 (t, 1H), 7.60 (d, 1H), 7.79 (d, 1H), 8.14 (s, 1H), 8.41 (s,1H).

Example 70 ethyl1-(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 1. The reaction time was 2 h. Proceeding from 200 mg (0.53 mmol)of ethyl1-(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 66A and 149 mg (0.59 mmol) of1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene, 253 mg (84% oftheory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.22 min; m/z=544 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 1.34 (s, 6H), 2.18 (s,3H), 2.45 (s, 3H), 3.93 (s, 2H), 4.19 (q, 2H), 5.06 (s, 2H), 7.19 (dd,1H), 7.33 (t, 1H), 7.40 (d, 2H), 7.59 (d, 1H), 8.13 (d, 1H), 8.39 (s,1H).

Example 71 ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-methyl-1H-benzotriazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

162 mg (0.51 mmol) of ethyl1-(1-methyl-1H-benzotriazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 74A were initially charged in 6.5 ml of DMF. 155 mg (0.56mmol) of 1-(bromomethyl)-2-chloro-3-(trifluoromethyl)benzene, 142 mg(1.03 mmol) of potassium carbonate and 9 mg (52 mol) of potassium iodidewere added and the reaction mixture was stirred at 60° C. for 5 h. Aftercooling to RT, water was added to the mixture. The precipitate wasfiltered off, washed with a little water and MTBE, and dried in a dryingcabinet at 50° C. This gave 149 mg (95% purity, 54% of theory) of thetitle compound.

LC-MS (Method 1): R_(t)=1.03 min; m/z=508 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 4.21 (q, 2H), 4.37 (s,3H), 5.17 (s, 2H), 7.51-7.57 (m, 1H), 7.61-7.65 (m, 1H), 7.71-7.75 (m,1H), 7.79-7.83 (m, 1H), 7.99-8.02 (m, 1H), 8.31-8.33 (m, 1H), 8.61 (s,1H).

Example 72 ethyl1-(1-methyl-1H-benzotriazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 71. Proceeding from 162 mg (0.51 mmol) of ethyl1-(1-methyl-1H-benzotriazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 74A and 143 mg (0.56 mmol) of1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene, 152 mg (59% oftheory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.02 min; m/z=488 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 2.47 (s, partlyconcealed by DMSO signal), 4.20 (q, 2H), 4.37 (s, 3H), 5.10 (s, 2H),7.33-7.39 (m, 1H), 7.40-7.45 (m, 1H), 7.58-7.64 (m, 1H), 7.73 (dd, 1H),8.00 (d, 1H), 8.32-8.34 (m, 1H), 8.58 (s, 1H).

Example 73 ethyl3-(2,3-dichlorobenzyl)-1-(1-methyl-1H-benzotriazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 71. Proceeding from 162 mg (0.51 mmol) of ethyl1-(1-methyl-1H-benzotriazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 74A and 136 mg (0.56 mmol) of 2,3-dichlorobenzyl bromide,188 mg (74% of theory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.99 min; m/z=474 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 4.20 (q, 2H), 4.37 (s,3H), 5.12 (s, 2H), 7.27 (d, 1H), 7.35 (t, 1H), 7.59 (d, 1H), 7.72 (d,1H), 8.00 (d, 1H), 8.32 (s, 1H), 8.59 (s, 1H).

Example 74 ethyl3-[3-chloro-2-(trifluoromethyl)benzyl]-1-(1-methyl-1H-benzotriazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

162 mg (0.51 mmol) of ethyl1-(1-methyl-1H-benzotriazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 74A were initially charged in DMF (6 ml), and 238 mg (65%purity, 0.56 mmol) of1-(bromomethyl)-3-chloro-2-(trifluoromethyl)benzene, 142 mg (1.03 mmol)of potassium carbonate and 8 mg (0.05 mmol) of potassium iodide wereadded. Subsequently, the reaction mixture was left to stir at 60° C. for5 h. The mixture cooled to RT was admixed with water and extracted twicewith ethyl acetate. The combined organic phases were washed with asaturated sodium chloride solution, dried over magnesium sulphate,filtered off and concentrated. The residue was stirred withcyclohexane/ethyl acetate, and the precipitated solid was filtered offwith suction and dried under reduced pressure. This gave 115 mg (43% oftheory) of the title compound.

LC-MS (Method 1): R_(t)=1.02 min; m/z=508 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 4.21 (q, 2H), 4.37 (s,3H), 5.23 (br.s, 2H), 7.36-7.41 (m, 1H), 7.58-7.67 (m, 2H), 7.70-7.75(m, 1H), 8.00 (d, 1H), 8.30-8.33 (m, 1H), 8.62 (s, 1H).

Example 75 ethyl1-(1-methyl-1H-indazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 1. The reaction time was 2 h. Proceeding from 200 mg (0.63 mmol)of ethyl1-(1-methyl-1H-indazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 75A and 177 mg (0.70 mmol) of1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene, 254 mg (80% oftheory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.11 min; m/z=487 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 2.46 (s, 3H), 4.10 (s,3H), 4.19 (q, 2H), 5.09 (s, 2H), 7.32-7.44 (m, 2H), 7.54 (d, 1H), 7.60(d, 1H), 7.78 (d, 1H), 7.98 (s, 1H), 8.18 (s, 1H), 8.49 (s, 1H).

Example 76 ethyl1-(1-methyl-1H-indazol-5-yl)-2,4-dioxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(R enantiomer)

200 mg (0.63 mmol) of ethyl1-(1-methyl-1H-indazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 75A and 500 mg (1.90 mmol) of triphenylphosphine wereinitially charged in THF/DMF 1:1 (8.4 ml) under argon and cooled to −30°C. 257 mg (1.27 mmol) of diisopropyl azodicarboxylate and a solution of154 mg (0.76 mmol) of (1S)-4-(trifluoromethyl)indan-1-ol from Example14A in 1 ml of THF were added dropwise. The reaction mixture was stirredat RT for 16 h. For workup, the reaction mixture was cooled to −40° C.,admixed with 1M hydrochloric acid, warmed to RT and extracted with ethylacetate. The organic phase was successively washed twice with 1Mhydrochloric acid and once with saturated sodium chloride solution,dried over magnesium sulphate and concentrated. The residue was purifiedby means of HPLC (Method 8). This gave 142 mg (43% of theory) of thetitle compound.

LC-MS (Method 1): R_(t)=1.11 min; m/z=499 (M+H)⁺.

¹H NMR (400 MHz, CDCl₃): δ [ppm]=1.36 (t, 3H), 2.40-2.52 (m, 1H),2.53-2.61 (m, 1H, partly concealed by DMSO signal), 3.08-3.19 (m, 1H),3.45-3.58 (m, 1H), 4.11 (s, 3H), 4.35 (q, 2H), 6.61-6.77 (m, 1H),7.23-7.33 (m, 3H, partly concealed by CDCl₃ signal), 7.44-7.53 (m, 2H),7.69 (s, 1H), 8.04 (s, 1H), 8.37 (s, 1H).

Specific optical rotation: α_(D) ²⁰=+146.6^(°), (chloroform, c=0.405g/100 ml).

Example 77 ethyl1-(1-methyl-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

1.00 g (3.18 mmol) of ethyl1-(1-methyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 76A were initially charged in DMF (8 ml), and 886 mg (3.50mmol) of 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene, 879 mg(6.36 mmol) of potassium carbonate and 53 mg (0.32 mmol) of potassiumiodide were added. Subsequently, the reaction mixture was left to stirat 60° C. for 5 h. The mixture cooled to RT was admixed with water, andthe precipitate was filtered off with suction, washed with water andethanol/MTBE, and dried under reduced pressure at 50° C. This gave 1.06g (68% of theory) of the title compound.

LC-MS (Method 1): R_(t)=0.93 min; m/z=487 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 2.46 (s, 3H), 3.89 (s,3H), 4.19 (q, 2H), 5.09 (s, 2H), 7.32-7.46 (m, 3H), 7.60 (d, 1H), 7.71(d, 1H), 7.89 (d, 1H), 8.33 (s, 1H), 8.46 (s, 1H).

Example 78 ethyl3-[3-chloro-2-(trifluoromethyl)benzyl]-1-(1-methyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 77. Proceeding from 200 mg (0.63 mmol) of ethyl1-(1-methyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 76A and 295 mg (65% purity, 0.70 mmol) of1-(bromomethyl)-3-chloro-2-(trifluoromethyl)benzene, 82 mg (26% oftheory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.97 min; m/z=507 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 3.89 (s, 3H), 4.20 (q,2H), 5.23 (s, 2H), 7.36 (d, 1H), 7.41-7.46 (m, 1H), 7.57-7.67 (m, 2H),7.70 (d, 1H), 7.87 (d, 1H), 8.32 (s, 1H), 8.49 (s, 1H).

Example 79 ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-methyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation of the title compound was analogous to Example 77.Proceeding from 200 mg (0.63 mmol) of ethyl1-(1-methyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 76A and 191 mg (0.70 mmol) of1-(bromomethyl)-2-chloro-3-(trifluoromethyl)benzene, after additionalpurification by means of preparative HPLC (Method 8), 153 g (47% oftheory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.97 min; m/z=507 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 3.89 (s, 3H), 4.20 (q,2H), 5.16 (s, 2H), 7.44 (dd, 1H), 7.50-7.56 (m, 1H), 7.59-7.63 (m, 1H),7.71 (d, 1H), 7.78-7.83 (m, 1H), 7.88 (d, 1H), 8.33 (s, 1H), 8.49 (s,1H).

Example 80 ethyl1-(1-ethyl-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

122.5 mg (0.37 mmol) of ethyl1-(1-ethyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 46A and 103 mg (0.41 mmol) of1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene were initiallycharged in DMF (4 ml), and 103 mg (0.74 mmol) of potassium carbonate and6 mg (0.04 mmol) of potassium iodide were added. The reaction mixturewas stirred at 60° C. for 5 h, then brought to RT and admixed withwater. The precipitate was filtered off with suction, washed with waterand MTBE, and dried under reduced pressure at 50° C. overnight. Thisgave 38 mg (19% of theory) of the title compound.

LC-MS (Method 1): R_(t)=0.97 min; m/z=501 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 1.43 (t, 3H), 2.46 (s,3H), 4.19 (q, 2H), 4.33 (q, 2H), 5.09 (s, 2H), 7.31-7.46 (m, 3H), 7.60(d, 1H), 7.76 (d, 1H), 7.89 (d, 1H), 8.40 (s, 1H), 8.48 (s, 1H), 8.48(s, 1H).

Example 81 ethyl1-(2-carbamoyl-1-methyl-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

158 mg (0.44 mmol) of ethyl1-(2-carbamoyl-1-methyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 81A were initially charged in DMF (3 ml), and 123 mg (0.48mmol) of 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene, 122 mg(0.88 mmol) of potassium carbonate and 7 mg (0.04 mmol) of potassiumiodide were added. The reaction mixture was left to stir at 80° C. for 1h. The cooled mixture was admixed with water, and the precipitated solidwas filtered off and washed with water. The filtrate was extracted twicewith dichloromethane, and the combined organic phases were dried overmagnesium sulphate, filtered off and concentrated. The residue wascombined with the previously isolated solid and purified by means ofpreparative HPLC (Method 8). This gave 131 mg (54% of theory) of thetitle compound.

LC-MS (Method 1): R_(t)=0.98 min; m/z=530 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 2.47 (s, partlyconcealed by DMSO signal), 4.16 (s, 3H), 4.20 (q, 2H), 5.10 (s, 2H),7.33-7.39 (m, 1H), 7.39-7.44 (m, 1H), 7.53-7.63 (m, 2H), 7.82 (d, 1H),7.92 (br.s, 1H), 7.96-8.00 (m, 1H), 8.32 (br. s, 1H), 8.50 (s, 1H).

Example 82 ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-methyl-1H-benzimidazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 80. The reaction time was 1 h. Proceeding from 150 mg (0.47mmol) of ethyl1-(1-methyl-1H-benzimidazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 82A and 143 mg (0.52 mmol) of1-(bromomethyl)-2-chloro-3-(trifluoromethyl)benzene, after additionalpurification by means of flash chromatography (dichloro-methane/methanol98:2), 110 mg (44% of theory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.92 min; m/z=507 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 3.87 (s, 3H), 4.20 (q,2H), 5.17 (s, 2H), 7.37 (dd, 1H), 7.54 (t, 1H), 7.61 (d, 1H), 7.77 (d,1H), 7.81 (d, 1H), 7.84 (d, 1H), 8.34 (s, 1H), 8.52 (s, 1H).

Example 83 ethyl1-(1-ethyl-2-methyl-1H-benzimidazol-5-yl)-3-[3-fluoro-2-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

200 mg (0.58 mmol) of ethyl1-(1-ethyl-2-methyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 117A were initially charged in DMF (7 ml) and admixed with165 mg (0.64 mmol) of1-(bromomethyl)-3-fluoro-2-(trifluoromethyl)benzene, 161 mg (1.17 mmol)of potassium carbonate and 10 mg (0.06 mmol) of potassium iodide. Thereaction mixture was left to stir at 60° C. for 5 h. The cooled mixturewas admixed with water, and the precipitated solid was filtered off andwashed with water. The solid was dissolved in dichloromethane andpurified by means of flash silica gel chromatography(dichloromethane/methanol, 30:1). This gave 153 mg (50% of theory) ofthe title compound.

LC-MS (Method 1): R_(t)=0.85 min; m/z=519 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 1.32 (t, 3H), 2.58 (s,3H), 4.19 (q, 2H), 4.28 (q, 2H), 5.21 (s, 2H), 7.22 (d, 1H), 7.33 (d,1H), 7.41 (t, 1H), 7.61-7.70 (m, 2H), 7.70-7.75 (m, 1H), 8.44-8.50 (m,1H).

Example 84 ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-ethyl-2-methyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 83. Proceeding from 200 mg (0.58 mmol) of ethyl1-(1-ethyl-2-methyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 117A and 175 mg (0.63 mmol) of1-(bromomethyl)-2-chloro-3-(trifluoromethyl)benzene, 114 mg (36% oftheory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.89 min; m/z=535 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 1.31 (t, 3H), 2.58 (s,3H), 4.19 (q, 2H), 4.27 (q, 2H), 5.16 (s, 2H), 7.35 (dd, 1H), 7.53 (t,1H), 7.60 (d, 1H), 7.65 (d, 1H), 7.73 (d, 1H), 7.80 (d, 1H), 8.47 (s,1H).

Example 85 ethyl1-(1-cyclohexyl-2-methyl-1H-benzimidazol-5-yl)-3-[3-fluoro-2-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 83. Proceeding from 200 mg (0.50 mmol) of ethyl1-(1-cyclohexyl-2-methyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 118A and 142 mg (0.55 mmol) of1-(bromomethyl)-3-fluoro-2-(trifluoromethyl)benzene, 90 mg (30% oftheory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.05 min; m/z=573 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 1.34-1.57 (m, 3H),1.67-1.75 (m, 1H), 1.82-1.92 (m, 4H), 2.10-2.23 (m, 2H), 2.60 (s, 3H),4.19 (q, 2H), 4.26-4.37 (m, 1H), 5.20 (s, 2H), 7.22 (d, 1H), 7.29 (dd,1H), 7.36-7.45 (m, 1H), 7.62-7.70 (m, 1H), 7.71 (d, 1H), 7.83 (d, 1H),8.47 (s, 1H).

Example 86 ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-isopropyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation of the title compound was analogous to Example 83.Proceeding from 200 mg (0.58 mmol) of ethyl1-(1-isopropyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 51A and 175 mg (0.64 mmol) of1-(bromomethyl)-2-chloro-3-(trifluoromethyl)benzene, after purificationby means of flash chromatography (dichloromethane/methanol 50:1), 64 mg(19% of theory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.05 min; m/z=535 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 1.56 (d, 6H), 4.19 (q,2H), 4.82 (spt, 1H), 5.16 (s, 2H), 7.42 (dd, 1H), 7.54 (t, 1H), 7.61 (d,1H), 7.80 (d, 2H), 7.88 (d, 1H), 8.49 (s, 1H), 8.51 (s, 1H).

Example 87 ethyl3-(2,3-dichlorobenzyl)-1-(1-isopropyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation of the title compound was analogous to Example 83.Proceeding from 200 mg (0.58 mmol) of ethyl1-(1-isopropyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 51A and 154 mg (0.64 mmol) of1-(bromomethyl)-2,3-dichlorobenzene, after purification by means offlash chromatography (dichloromethane/methanol 50:1), 83 mg (28% oftheory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.02 min; m/z=501 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 1.56 (d, 6H), 4.19 (q,2H), 4.82 (spt, 1H), 5.11 (s, 2H), 7.26 (d, 1H), 7.34 (t, 1H), 7.42 (dd,1H), 7.58 (d, 1H), 7.79 (d, 1H), 7.88 (d, 1H), 8.49 (s, 2H).

Example 88 ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-cyclobutyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

Preparation of the title compound was analogous to Example 83, using 200mg (0.56 mmol) of ethyl1-(1-cyclobutyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 41A and 169 mg (0.62 mmol) of1-(bromomethyl)-2-chloro-3-(trifluoromethyl)benzene. For workup, thereaction mixture was admixed with water, and the precipitate wasfiltered off with suction, washed with water and MTBE, and dried underreduced pressure at 50° C. overnight. The solid was purified by means offlash chromatography (dichloromethane/methanol 70:1). Theproduct-containing fractions were concentrated, and the residue wassubjected to extractive stirring in ethanol, filtered off, washed withethanol and dried under high vacuum. This gave 141 mg (42% of theory) ofthe title compound.

LC-MS (Method 1): R_(t)=1.06 min; m/z=547 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 1.86-1.96 (m, 2H), 2.56(s, 4H, partly concealed by DMSO signal), 4.20 (q, 2H), 5.04 (quin, 1H),5.16 (s, 2H), 7.42 (dd, 1H), 7.53 (t, 1H), 7.62 (d, 1H), 7.74 (d, 1H),7.81 (d, 1H), 7.89 (d, 1H), 8.50 (s, 1H), 8.55 (s, 1H).

Example 89 ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-methyl-1H-indazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 80. Proceeding from 200 mg (0.63 mmol) of ethyl1-(1-methyl-1H-indazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 75A and 191 mg (0.70 mmol) of1-(bromomethyl)-2-chloro-3-(trifluoromethyl)benzene, 228 mg (67% oftheory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.11 min; m/z=507 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.24 (t, 3H), 4.10 (s, 3H), 4.20 (q,2H), 5.16 (s, 2H), 7.49-7.57 (m, 2H), 7.62 (d, 1H), 7.74-7.84 (m, 2H),7.98 (d, 1H), 8.18 (s, 1H), 8.52 (s, 1H).

Example 90 ethyl1-(1-ethyl-1H-benzimidazol-5-yl)-3-[3-fluoro-2-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 1. Proceeding from 122.5 mg (0.37 mmol) of ethyl1-(1-ethyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 46A and 105 mg (0.41 mmol) of1-(bromomethyl)-3-fluoro-2-(trifluoromethyl)-benzene, 73 mg (35% oftheory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=0.92 min; m/z=505 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 1.43 (t, 3H), 4.20 (q,2H), 4.33 (q, 2H), 5.21 (br. s, 2H), 7.22 (d, 1H), 7.36-7.46 (m, 2H),7.67 (q, 1H), 7.76 (d, 1H), 7.84-7.90 (m, 1H), 8.40 (s, 1H), 8.51 (s,1H).

Example 91 ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-ethyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation of the title compound was analogous to Example 80.Proceeding from 122.5 mg (0.37 mmol) of ethyl1-(1-ethyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 46A and 112 mg (0.41 mmol) of1-(bromomethyl)-2-chloro-3-(trifluoromethyl)benzene, after additionalpurification by means of flash chromatography (dichloromethane/methanol30:1), 52 mg (27% of theory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.01 min; m/z=521 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 1.43 (t, 3H), 4.20 (q,2H), 4.34 (q, 2H), 5.16 (s, 2H), 7.43 (dd, 1H), 7.53 (t, 1H), 7.61 (d,1H), 7.76 (d, 1H), 7.81 (d, 1H), 7.88 (d, 1H), 8.40 (s, 1H), 8.50 (s,1H).

Example 92 ethyl3-[3-chloro-2-(trifluoromethyl)benzyl]-1-[1-(cyclopropylmethyl)-1H-benzimidazol-5-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

200 mg (0.56 mmol) of ethyl1-[1-(cyclopropylmethyl)-1H-benzimidazol-5-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 56A were initially charged in 7.1 ml of DMF. 156 mg (1.13mmol) of potassium carbonate, 9 mg (0.05 mmol) of potassium iodide and261 mg (65% purity, 0.62 mmol) of1-(bromomethyl)-3-chloro-2-(trifluoromethyl)benzene were added and themixture was heated to 60° C. for 5 h. The cooled reaction mixture wasadmixed with water, extracted twice with ethyl acetate, and the combinedorganic phases were washed with saturated sodium chloride solution,dried over magnesium sulphate and concentrated. The residue was stirredin ethanol, and the precipitated solid was filtered off with suction anddried at the high-vacuum pump. This gave 137 mg (44% of theory) of thetitle compound. The filtrate was concentrated and the residue waspurified by means of flash chromatography (dichloromethane/methanol50:1). It was thus possible to isolate an additional 56 mg of the titlecompound (overall yield 61% of theory).

LC-MS (Method 3): R_(t)=1.29 min; m/z=547 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=0.40-0.48 (m, 2H), 0.51-0.58 (m, 2H),1.23 (t, 3H), 1.27-1.37 (m, 1H), 4.14-4.24 (m, 4H), 5.23 (s, 2H), 7.36(d, 1H), 7.42 (dd, 1H), 7.56-7.68 (m, 2H), 7.81 (d, 1H), 7.87 (d, 1H),8.43 (s, 1H), 8.53 (s, 1H).

Example 93 ethyl1-(1-isopropyl-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation of the title compound was analogous to Example 80.Proceeding from 200 mg (0.58 mmol) of ethyl1-(1-isopropyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 51A and 162 mg (0.64 mmol) of1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene, after additionalpurification by means of flash chromatography (dichloromethane/methanol50:1), 90 mg (29% of theory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.04 min; m/z=515 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 1.56 (d, 6H), 2.46 (s,3H), 4.19 (q, 2H), 4.82 (spt, 1H), 5.09 (s, 2H), 7.32-7.46 (m, 3H), 7.60(d, 1H), 7.80 (d, 1H), 7.89 (d, 1H), 8.48 (d, 2H).

Example 94 ethyl1-(1,3-dimethyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)-benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 1. The reaction time was 2 h. Proceeding from 160 mg (0.42 mmol)of ethyl1-(1,3-dimethyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 87A and 117 mg (0.46 mmol) of1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene, 195 mg (84% oftheory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.10 min; m/z=553 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 2.46 (s, 3H), 3.26 (s,3H), 3.30 (s, 3H), 4.20 (q, 2H), 5.08 (s, 2H), 7.15 (d, 1H), 7.23 (dd,1H), 7.29 (d, 1H), 7.31-7.39 (m, 2H), 7.58-7.63 (m, 1H), 8.45 (s, 1H).

Example 95 ethyl3-[3-chloro-2-(trifluoromethyl)benzyl]-1-(1,3-dimethyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 1. The reaction time was 2 h. Proceeding from 160 mg (0.42 mmol)of ethyl1-(1,3-dimethyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 87A and 194 mg (65% purity, 0.46 mmol) of1-(bromomethyl)-3-chloro-2-(trifluoromethyl)benzene (preparation: see WO2004/52858, page 149, Example 176), after additional purification bymeans of flash chromatography (dichloromethane/methanol 250:1), 120 mg(50% of theory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.11 min; m/z=573 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 3.27 (s, 3H), 3.30 (s,3H), 4.20 (q, 2H), 5.21 (br.s, 2H), 7.17 (d, 1H), 7.21 (dd, 1H), 7.26(d, 1H), 7.32 (d, 1H), 7.56-7.67 (m, 2H), 8.49 (s, 1H).

Example 96 ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1,3-dimethyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 1. Proceeding from 160 mg (0.42 mmol) of ethyl1-(1,3-dimethyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 87A and 126 mg (0.46 mmol) of1-(bromomethyl)-2-chloro-3-(trifluoromethyl)benzene, 167 mg (69% oftheory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.11 min; m/z=573 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 3.27 (s, 3H), 3.31 (s,3H), 4.20 (q, 2H), 5.15 (s, 2H), 7.16 (d, 1H), 7.22 (dd, 1H), 7.27 (d,1H), 7.49-7.60 (m, 2H), 7.80 (d, 1H), 8.48 (s, 1H).

Example 97 ethyl1-(1,3-dimethyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl)-2,4-dioxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(R enantiomer)

The preparation and purification of the title compound were analogous toExample 42 (Method A). Proceeding from 200 mg (0.52 mmol) of ethyl1-(1,3-dimethyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 87A and 127 mg (0.63 mmol) of(1S)-4-(trifluoromethyl)indan-1-ol from Example 14A, 149 mg (50% oftheory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.15 min; m/z=565 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 2.35-2.43 (m, 1H),2.43-2.48 (m, 1H, partly concealed by DMSO signal), 3.03-3.15 (m, 1H),3.22-3.27 (m, 4H), 3.29 (s, 3H), 4.17 (q, 2H), 6.31-6.59 (m, 1H),7.09-7.31 (m, 3H), 7.36 (t, 1H), 7.47 (d, 1H), 7.53 (d, 1H), 8.37 (s,1H).

Example 98 ethyl1-(1,3-benzothiazol-6-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 80. Proceeding from 200 mg (0.63 mmol) of ethyl1-(1,3-benzothiazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 88A and 175 mg (0.69 mmol) of1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene, 204 mg (65% oftheory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.08 min; m/z=490 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 2.46 (s, 3H), 4.20 (q,2H), 5.10 (s, 2H), 7.36 (t, 1H), 7.42 (d, 1H), 7.60 (d, 1H), 7.73 (dd,1H), 8.22 (d, 1H), 8.41 (d, 1H), 8.59 (s, 1H), 9.54 (s, 1H).

Example 99 ethyl1-(4-methylquinolin-7-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 80. Proceeding from 200 mg (0.61 mmol) of ethyl1-(4-methylquinolin-7-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 93A and 171 mg (0.67 mmol) of1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene, 230 mg (75% oftheory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.13 min; m/z=498 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.24 (t, 3H), 2.47 (s, 3H), 2.74 (s,3H), 4.21 (q, 2H), 5.11 (s, 2H), 7.33-7.39 (m, 1H), 7.43-7.47 (m, 1H),7.48-7.51 (m, 1H), 7.59-7.63 (m, 1H), 7.77-7.81 (m, 1H), 8.22-8.27 (m,2H), 8.62 (s, 1H), 8.85 (d, 1H).

Example 100 ethyl1-(1-methyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 1. The reaction time was about 16 h. Proceeding from 200 mg(0.57 mmol) of ethyl1-(1-methyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 92A and 161 mg (0.63 mmol) of1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene, 255 mg (85% oftheory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.07 min; m/z=518 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 2.46 (s, 3H), 3.30 (s,partly concealed by water signal), 4.20 (q, 2H), 5.07 (s, 2H), 5.30 (s,2H), 7.24 (d, 1H), 7.30-7.41 (m, 2H), 7.47 (d, 1H), 7.54-7.62 (m, 2H),8.44 (s, 1H).

Example 101 ethyl1-(1-methyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-2,4-dioxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 67. Proceeding from 200 mg (0.56 mmol) of ethyl1-(1-methyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 92A and 140 mg (0.69 mmol) of(1S)-4-(trifluoromethyl)indan-1-ol from Example 14A, after purificationby means of HPLC (Method 8), 160 mg (51% of theory) of the titlecompound were obtained.

LC-MS (Method 1): R_(t)=1.07 min; m/z=530 (M+H)⁺.

¹H NMR (400 MHz, CDCl₃): δ [ppm]=1.36 (t, 3H), 2.37-2.48 (m, 1H),2.53-2.60 (m, 1H), 3.08-3.19 (m, 1H), 3.39 (s, 3H), 3.45-3.58 (m, 1H),4.36 (q, 2H), 5.21 (s, 2H), 6.61-6.73 (m, 1H), 7.03 (d, 1H), 7.13 (s,1H), 7.26 (d, 3H, partly concealed by CHCl₃ signal), 7.47 (d, 1H),8.26-8.30 (m, 1H). Specific optical rotation: α_(D) ²⁰=+124.4°,(chloroform, c=0.360 g/100 ml).

Example 102 ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 80. Proceeding from 200 mg (0.58 mmol) of ethyl1-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 91A and 162 mg (0.64 mmol) of1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene, 267 mg (89% oftheory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.06 min; m/z=516 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 2.46 (s, 3H), 2.58 (t,2H), 2.92 (t, 2H), 3.28 (s, 3H), 4.19 (q, 2H), 5.08 (s, 2H), 7.22 (d,1H), 7.31-7.39 (m, 2H), 7.40-7.46 (m, 2H), 7.60 (d, 1H), 8.41 (s, 1H).

Example 103 ethyl1-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2,4-dioxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(R enantiomer)

200 mg (0.58 mmol) of ethyl1-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 91A and 475 mg (1.81 mmol) of triphenylphosphine wereinitially charged in THF/DMF 1:1 (7.6 ml) under argon. 235 mg (1.16mmol) of diisopropyl azodicarboxylate were added dropwise and then 141mg (0.69 mmol) of (1S)-4-(trifluoromethyl)indan-1-ol from Example 14Awere added. The reaction mixture was stirred at RT for 16 h. For workup,the mixture was admixed with 1M hydrochloric acid and diluted with ethylacetate, and phases were separated. The organic phase was successivelywashed twice with 1M hydrochloric acid and once with saturated sodiumchloride solution, dried over magnesium sulphate, filtered andconcentrated. The residue was purified by means of preparative HPLC(Method 8). This gave 125 mg (40% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.09 min; m/z=528 (M+H)⁺.

¹H NMR (400 MHz, CDCl₃): δ [ppm]=1.36 (t, 3H), 2.38-2.50 (m, 1H),2.53-2.61 (m, 1H, partly concealed by DMSO signal), 2.67 (t, 2H), 2.94(t, 2H), 3.08-3.19 (m, 1H), 3.36 (s, 3H), 3.46-3.58 (m, 1H), 4.36 (q,2H), 6.62-6.74 (m, 1H), 7.05 (d, 1H), 7.13 (s, 1H), 7.18-7.23 (m, 1H),7.24-7.30 (m, 2H), 7.47 (d, 1H), 8.29 (s, 1H). Specific opticalrotation: α_(D) ²⁰=+128.5°, (chloroform, c=0.415 g/100 ml).

Example 104 ethyl1-(6-fluoro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(R enantiomer)

200 mg (0.55 mmol) of ethyl1-(6-fluoro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 95A and 434 mg (1.66 mmol) of triphenylphosphine wereinitially charged in THF/DMF 1:1 (7.3 ml) under argon and cooled to −30°C. 218 μl (1.10 mmol) of diisopropyl azodicarboxylate, then a solutionof 134 mg (0.66 mmol) of (1S)-4-(trifluoromethyl)indan-1-ol from Example14A in 3 ml of THF, were added dropwise. The reaction mixture was warmedto RT and stirred at RT for 30 min. For workup, the reaction mixture wascooled to 0° C., admixed with 5 ml of 1M hydrochloric acid, thenextracted at RT with ethyl acetate. The organic phase was successivelywashed twice with 1M hydrochloric acid and once with saturated sodiumchloride solution, dried over magnesium sulphate and concentrated. Theresidue was subjected to extractive stirring with ethanol, and theprecipitated solid was filtered off with suction and discarded. Thefiltrate was concentrated on a rotary evaporator, dissolved in a littledichloromethane and purified by means of flash chromatography (eluent:dichloromethane/methanol 120:1→20:1). The resulting product was driedunder HV, then stirred in 10 ml of cyclohexane/ethyl acetate 1:1. Thesolid was filtered off and dried under HV. This gave 146 mg (47% oftheory) of the title compound.

LC-MS (Method 1): R_(t)=1.10 min; m/z=547 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 2.30-2.42 (m, 1H),2.52-2.53 (m, 1H, partly concealed by DMSO signal), 3.04-3.15 (m, 1H),3.22-3.30 (m, 1H), 3.32 (s, 3H), 3.35 (s, 3H), 4.19 (q, 2H), 6.37-6.57(m, 1H), 7.33-7.50 (m, 4H), 7.54 (d, 1H), 8.48 (s, 1H).

Example 105 ethyl3-[(3-chloro-4-methyl-2-thienyl)methyl]-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

45 μl (0.23 mmol) of diisopropyl azodicarboxylate were added dropwise toa solution, initially charged under argon, of 33 mg (0.20 mmol) of(3-chloro-4-methyl-2-thienyl)methanol from Example 96A and 74 mg (0.28mmol) in 2 ml of anhydrous THF at RT. After 5 min, 65 mg (0.18 mmol) ofethyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 2A were added and the reaction mixture was stirred at RTovernight. For workup, 3 drops of 1N hydrochloric acid were added andthe entire reaction mixture was separated by means of preparative HPLC(Method 8). The product-containing fractions were concentrated on arotary evaporator and the residue was stirred in diethyl ether. Thesolid was filtered off with suction and dried under high vacuum. Thisgave 26 mg (26% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.00 min; m/z=489 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 2.12 (s., 3H), 3.30(s., 3H, partly concealed by water signal), 3.37 (s, 3H), 4.19 (q, 2H),5.19 (s., 2H), 7.14-7.23 (m, 1H), 7.24-7.32 (m, 2H), 7.38 (s, 1H), 8.36(s, 1H).

Example 106 ethyl3-(4,6-difluoro-2,3-dihydro-1H-inden-1-yl)-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate)

229 μl (1.16 mmol) of diisopropyl azodicarboxylate were added dropwiseto a solution, initially charged under argon at −40° C., of 200 mg (0.58mmol) of ethyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 2A and 457 mg (1.74 mmol) of triphenylphosphine in 16 ml ofTHF/DMF 1:1. 128 mg (1.16 mmol) of 4,6-difluoroindan-1-ol from Example97A were added. The reaction mixture was warmed to RT and stirredfurther overnight. For workup, while cooling with ice, 5 ml of 1Nhydrochloric acid were added, and the mixture was stirred further for 15min, then extracted with ethyl acetate. The organic phase was washedtwice with 1N hydrochloric acid, twice with a saturated sodiumhydrogencarbonate solution, then with a saturated sodium chloridesolution, then dried over sodium sulphate and concentrated on a rotaryevaporator. The residue was purified by means of preparative HPLC(Method 8). This gave 178 mg (61% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.01 min; m/z=497 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 2.35-2.48 (m, 2H),2.84-2.96 (m, 1H), 3.02-3.16 (m, 1H), 3.31 (s, 3H), 3.37 (s, 3H), 4.18(q, 2H), 6.25-6.55 (m, 1H), 6.93-7.08 (m, 2H), 7.13-7.30 (m, 2H),7.31-7.45 (m, 1H), 8.33 (s, 1H).

Example 107 ethyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-(6-methyl-2,3-dihydro-1H-inden-1-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate)

The preparation and purification of the title compound were analogous toExample 106. Proceeding from 200 mg (0.58 mmol) of ethyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 2A and 112 mg (0.75 mmol) of 6-methylindan-1-ol fromExample 100A, 130 mg (47% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.02 min; m/z=475 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.21 (t, 3H), 2.25 (s, 3H), 2.31-2.43(m, 2H), 2.79-2.91 (m, 1H), 3.04-3.18 (m, 1H), 3.31 (s, 3H), 3.37 (s,3H), 4.17 (q, 2H), 6.24-6.51 (m, 1H), 6.93-7.01 (m, 2H), 7.09 (d, 1H),7.14-7.29 (m, 2H), 7.31-7.47 (m, 1H), 8.31 (s, 1H).

Example 108 ethyl3-(4,6-difluoro-2,3-dihydro-1H-inden-1-yl)-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate)

Preparation of the title compound was analogous to Example 103, but witha reaction time of 1 h, proceeding from 200 mg (0.57 mmol) of ethyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 31A and 127 mg (0.74 mmol) of 4,6-difluoroindan-1-ol fromExample 97A. The product was purified by preparative HPLC (Method 7).This gave 173 mg (57% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.10 min; m/z=500 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 2.35-2.48 (m, 2H),2.84-2.96 (m, 1H), 3.00-3.15 (m, 1H), 3.44 (s, 3H), 4.18 (q, 2H),6.27-6.52 (m, 1H), 6.93-7.07 (m, 2H), 7.39-7.65 (m, 2H), 7.76-7.92 (m,1H), 8.40 (s, 1H).

Example 109 ethyl3-(6-methyl-2,3-dihydro-1H-inden-1-yl)-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate)

The preparation and purification of the title compound were analogous toExample 108. Proceeding from 200 mg (0.57 mmol) of ethyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 31A and 111 mg (0.74 mmol) of 6-methylindan-1-ol fromExample 100A, 131 mg (47% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.11 min; m/z=478 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 2.24 (s, 3H), 2.31-2.43(m, 2H), 2.79-2.91 (m, 1H), 3.01-3.17 (m, 1H), 3.44 (s, 3H), 4.17 (q,2H), 6.21-6.51 (m, 1H), 6.91-7.02 (m, 2H), 7.09 (d, 1H), 7.42 (d, 1H),7.48-7.63 (m, 1H), 7.77-7.92 (m, 1H), 8.38 (s, 1H).

Example 110 ethyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[6-fluoro-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate)

The preparation and purification of the title compound were analogous toExample 108. Proceeding from 60 mg (0.17 mmol) of ethyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 2A and 50 mg (0.22 mmol) of6-fluoro-4-(trifluoromethyl)indan-1-ol from Example 98A, 68 mg (71% oftheory) of the title compound were obtained.

LC-MS (Method 4): R_(t)=2.38 min; m/z=547 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.23 (t, 3H), 2.33-2.46 (m, 1H),2.48-2.60 (m, 1H), 2.95-3.07 (m, 1H), 3.26-3.40 (m, 7H), 4.21 (q, 2H),6.47-6.57 (m, 1H), 6.86 (s, 1H), 6.92-7.01 (m, 3H), 7.08-7.17 (m, 1H),8.24 (s, 1H).

Example 111 tert-butyl6-[5-(ethoxycarbonyl)-2,4-dioxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3,4-dihydropyrimidin-1(2H)-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate(R enantiomer)

The preparation and purification of the title compound were analogous toExample 108, with initial ice bath cooling. Proceeding from 2.50 g (5.80mmol) of tert-butyl6-[5-(ethoxycarbonyl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylatefrom Example 101A and 1.29 g (6.39 mmol) of4-(trifluoromethyl)indan-1-ol (S enantiomer) from Example 14A, 2.29 g(61% of theory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.24 min; m/z=615 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.21 (t, 3H), 1.56 (s, 9H), 2.35-2.43(m, 1H), 2.43-2.48 (m, 1H), 3.02-3.14 (m, 1H), 3.21-3.30 (m, 1H), 3.32(br.s, 3H), 4.18 (q, 2H), 6.33-6.59 (m, 1H), 7.26-7.45 (m, 3H),7.46-7.58 (m, 2H), 7.77-7.96 (m, 1H), 8.32 (s, 1H).

Example 112 ethyl1-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(R enantiomer)

2.29 g (3.73 mmol) of the compound from Example 111 were stirred in 50ml of dichloromethane and 50 ml of trifluoroacetic acid at RT for 1 h.The reaction mixture was concentrated to dryness on a rotary evaporator.The residue was admixed with ethyl acetate and a 1M sodium carbonatesolution. The organic phase was separated, washed with a saturatedsodium chloride solution, dried over sodium sulphate and concentrated ona rotary evaporator. The residue was dried under HV. This gave 1.66 g(84% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.03 min; m/z=515 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 2.34-2.55 (m, 2H),3.01-3.15 (m, 1H), 3.21-3.33 (m, 1H), 3.30 (s, 3H), 4.17 (q, 2H), 6.46(br. m., 1H), 7.06-7.23 (m, 2H), 7.36 (t, 1H), 7.45-7.55 (m, 2H), 8.31(s, 1H), 11.12 (br.s, 1H).

Example 113 ethyl1-(3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(R enantiomer)

100 mg (0.19 mmol) of ethyl1-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(R enantiomer) from Example 112 were initially charged in DMF (3 ml). 36mg (0.23 mmol) of iodoethane and 126 mg (0.38 mmol) of caesium carbonatewere added. The reaction mixture was left to stir at 60° C. for 1 h. Thereaction mixture cooled to RT was filtered and the filtrate was purifiedby preparative HPLC (Method 7). This gave 77 mg (72% of theory) of thetitle compound.

LC-MS (Method 4): R_(t)=2.40 min; m/z=543 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.22 (t, 6H), 2.31-2.45 (m, 1H),2.45-2.56 (m, 1H), 2.99-3.12 (m, 1H), 3.32 (s, 3H), 3.35-3.43 (m, 1H),3.82 (q, 2H), 4.20 (q, 2H), 6.48-6.59 (m, 1H), 6.88 (s, 1H), 6.91-6.98(m, 2H), 7.17-7.29 (m, 2H), 7.41 (d, 1H), 8.24 (s, 1H).

Example 114 ethyl1-(3-isopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(R enantiomer)

The preparation and purification of the title compound were analogous toExample 113. Proceeding from 200 mg (0.30 mmol) of ethyl1-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(R enantiomer) from Example 112 and 79 mg (0.46 mmol) of 2-iodopropane,125 mg (57% of theory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.17 min; m/z=557 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.23 (t, 3H), 1.40-1.44 (m, 6H),2.31-2.43 (m, 1H), 2.45-2.57 (m, 1H), 3.00-3.12 (m, 1H), 3.30 (s, 3H),3.34-3.46 (m, 1H), 4.20 (q, 2H), 4.49-4.59 (m, 1H), 6.47-6.60 (m, 1H),6.93 (s, 3H), 7.17-7.28 (m, 2H), 7.41 (d, 1H), 8.23 (s, 1H).

Example 115 ethyl1-[1-methyl-2-oxo-3-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydro-1H-benzimidazol-5-yl]-2,4-dioxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(diastereomer mixture)

The preparation and purification of the title compound were analogous toExample 113, with a reaction time of 16 h. Proceeding from 250 mg (0.48mmol) of ethyl1-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(R enantiomer) from Example 112 and 112 mg (0.58 mmol) of3-bromo-1,1,1-trifluoropropan-2-ol (racemate), 186 mg (57% of theory) ofthe title compound were obtained.

LC-MS (Method 1): R_(t)=1.10 min; m/z=627 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.23 (t, 3H), 2.28-2.43 (m, 1H),2.44-2.57 (m, 1H), 2.98-3.12 (m, 1H), 3.33-3.44 (m, 4H), 4.00-4.10 (m,1H), 4.11-4.24 (m, 3H), 4.25-4.47 (m, 2H), 6.47-6.60 (m, 1H), 6.94-7.06(m, 3H), 7.17-7.29 (m, 2H), 7.41 (d, 1H), 8.21 (s, 1H).

Example 116 ethyl1-[1-methyl-2-oxo-3-(3,3,3-trifluoropropyl)-2,3-dihydro-1H-benzimidazol-5-yl]-2,4-dioxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(R enantiomer)

250 mg (0.48 mmol) of ethyl1-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(R enantiomer) from Example 112, 317 mg (0.97 mmol) of caesiumcarbonate, 2 mg (12 mol) of potassium iodide and 103 mg (0.58 mmol) of3-bromo-1,1,1-trifluoropropane in 7.5 ml of DMF were stirred at 60° C.Since conversion after 16 h was inadequate, an additional 1 eq. each ofcaesium carbonate and 3-bromo-1,1,1-trifluoropropane were added after 16h and again after 40 h, and the mixture was stirred at 60° C. overnight.Subsequently, the reaction mixture cooled to RT was diluted with ethylacetate and washed twice with 1 N hydrochloric acid. The organic phasewas dried over sodium sulphate and the solvent was removed on a rotaryevaporator. The residue was stirred in MTBE and the solid formed wasfiltered off with suction. The solid was unreacted reactant (88 mg). Thefiltrate was concentrated and the residue was purified by preparativeHPLC (Method 7). This gave 106 mg (35% of theory) of the title compound.

LC-MS (Method 5): Rt=1.19 min; m/z=611 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 2.36-2.44 (m, 1H),2.44-2.48 (m, 1H), 2.69-2.82 (m, 2H), 3.03-3.15 (m, 1H), 3.23-3.30 (m,1H), 3.37 (s, 3H), 4.10 (t, 2H), 4.18 (q, 2H), 6.36-6.55 (m, 1H),7.17-7.32 (m, 2H), 7.37 (t, 1H), 7.45-7.51 (m, 2H), 7.51-7.56 (m, 1H),8.35 (s, 1H).

Example 117 ethyl1-(3-cyclopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(R enantiomer)

A mixture of 100 mg (0.19 mmol) of the compound from Example 112, 33.4mg (0.39 mmol) of cyclopropylboronic acid, 24 mg (0.19 mmol) ofcopper(I) acetate, 41.2 mg (0.39 mmol) of sodium carbonate, 31 μl (0.39mmol) of pyridine in 2 ml of toluene was stirred at 70° C. for 6 h.Subsequently, the reaction mixture cooled to RT was diluted with ethylacetate and washed twice with 1 N hydrochloric acid. The organic phasewas dried over sodium sulphate and the solvent was removed on a rotaryevaporator. The residue was purified by preparative HPLC (Method 8).This gave 90 mg (84% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.09 min; m/z=555 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=0.92-1.01 (m, 2H), 1.04-1.11 (m, 2H),1.31 (t, 3H), 2.39-2.51 (m, 1H), 2.53-2.65 (m, 1H), 2.86 (br. spt, 1H),3.08-3.21 (m, 1H), 3.36 (s, 3H), 3.42-3.55 (m, 1H), 4.29 (q, 2H),6.55-6.68 (m, 1H), 6.96-7.05 (m, 2H), 7.11-7.16 (m, 1H), 7.27-7.32 (m,1H), 7.33 (d, 1H), 7.49 (d, 1H), 8.32 (s, 1H).

Example 118 ethyl1-[3-(cyanomethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]-2,4-dioxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(R enantiomer)

200 mg (0.38 mmol) of ethyl1-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(R enantiomer) from Example 112 were initially charged in acetonitrile(3.7 ml), and 93 mg (0.77 mmol) of bromoacetonitrile and 161 mg (1.16mmol) of potassium carbonate were added. The reaction mixture was leftto stir at 70° C. for 2 h. The reaction mixture cooled to RT was admixedwith 3 ml of 1 N hydrochloric acid and stirred for 10 min. The wholemixture was separated directly by preparative HPLC (Method 7). This gave180 mg (83% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.09 min; m/z=554 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 2.38-2.47 (m, 2H),3.03-3.15 (m, 1H), 3.23-3.28 (m, 1H), 3.40 (s, 3H), 4.17 (q, 2H), 5.13(s, 2H), 6.35-6.56 (m, 1H), 7.26-7.40 (m, 3H), 7.46-7.61 (m, 3H), 8.36(s, 1H).

Example 119 ethyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-3-[7-(trifluoromethyl)-2,3-dihydro-1-benzofur-3-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate)

The preparation and purification of the title compound were analogous toExample 108. Proceeding from 71 mg (0.20 mmol) of ethyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 31A and 50 mg (0.24 mmol) of7-(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-ol (racemate) fromExample 99A, 35 mg (31% of theory) of the title compound were obtained.

LC-MS (Method 4): R_(t)=2.35 min; m/z=534 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.24 (t, 3H), 3.37 (s, 3H), 4.22 (q,2H), 4.69-4.75 (m, 1H), 4.79 (t, 1H), 6.75-6.82 (m, 1H), 6.87 (t, 1H),7.05 (d, 1H), 7.22 (dd, 1H), 7.30 (d, 1H), 7.33-7.38 (m, 2H), 8.21 (s,1H).

Example 120 ethyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-(5-methoxy-2,3-dihydro-1H-inden-1-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate)

Under an argon atmosphere, 200 mg (0.58 mmol) of the compound fromExample 2A and 457 mg (1.74 mmol) of triphenylphosphine were initiallycharged in 8 ml of DMF and 8 ml of THF and cooled to −40° C. 229 μl(1.16 mmol) of diisopropyl azodicarboxylate were added dropwise, then155 mg (80% purity, 0.76 mmol) of the compound from Example 102A. Thecooling bath was removed and the mixture was stirred at RT overnight.Subsequently, 25 ml of 1N hydrochloric acid were added and the mixturewas stirred for a further 15 min. For workup, while cooling with ice, 5ml of 1N hydrochloric acid were added to the reaction mixture, and themixture was stirred further for 15 min, then extracted with ethylacetate. The organic phase was washed twice with 1N hydrochloric acid,twice with a saturated sodium hydrogencarbonate solution, then with asaturated sodium chloride solution, then dried over sodium sulphate andconcentrated on a rotary evaporator. The residue was purified bypreparative HPLC (Method 7). This gave 89 mg (30% of theory) of thetitle compound.

LC-MS (Method 1): R_(t)=0.96 min; m/z=491 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 2.24-2.48 (m, 2H),2.80-2.96 (m, 1H), 3.09-3.21 (m, 1H), 3.31 (s, 3H), 3.36 (s, 3H), 3.72(s, 3H), 4.17 (q, 2H), 6.25-6.48 (m, 1H), 6.69 (dd, 1H), 6.78 (s, 1H),7.04 (d, 1H), 7.10-7.29 (m, 2H), 7.37 (br.s, 1H), 8.30 (s, 1H).

Example 1211-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

5.60 g (10.84 mmol) of ethyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)-benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 1 were initially charged in 78 ml of glacial acetic acidand 39 ml of conc. hydrochloric acid and stirred at 120° C. for 1 h.Subsequently, the mixture cooled to RT was admixed with water and theprecipitate was filtered off with suction. The solid was washedsuccessively with water and MTBE and then dried at 50° C. under reducedpressure. This gave 5.11 g (96% of theory) of the title compound.

LC-MS (Method 1): R_(t)=0.98 min; m/z=489 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.47 (s, 3H), 3.31 (s, 3H), 3.37 (s,3H), 5.11 (s, 2H), 7.22-7.30 (m, 2H), 7.33-7.43 (m, 3H), 7.59-7.63 (m,1H), 8.45 (s, 1H), 12.73 (br.s, 1H).

Example 1223-[2,3-bis(trifluoromethyl)benzyl]-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were analogous toExample 121. Proceeding from 114 mg (0.20 mmol) of ethyl3-[2,3-bis(trifluoromethyl)benzyl]-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 8, 92 mg (85% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.01 min; m/z=543 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.34 (s, 3H), 3.37 (s, 3H), 5.27 (m,2H), 7.22-7.30 (m, 2H), 7.37-7.40 (m, 1H), 7.73-7.77 (m, 1H), 7.82-7.88(m, 1H), 7.96-8.00 (m, 1H), 8.47 (s, 1H), 12.73 (br.s, 1H).

Example 1233-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were analogous toExample 121. Proceeding from 200 mg (0.37 mmol) of ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 2, 67 mg (88% of theory) of the title compound wereobtained.

LC-MS (Method 3): R_(t)=1.21 min; m/z=509 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.34 (s, 3H), 3.37 (s, 3H), 5.18 (s,2H), 7.22-7.30 (m, 2H), 7.38-7.41 (m, 1H), 7.51-7.57 (m, 1H), 7.58-7.63(m, 1H), 7.78-7.83 (m, 1H), 8.47 (s, 1H), 12.72 (br.s, 1H).

Example 1243-(2,3-dichlorobenzyl)-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 200 mg (0.40 mmol) of ethyl3-(2,3-dichlorobenzyl)-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 3, 147 mg (78% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.00 min; m/z=475 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.34 (s, 3H), 3.37 (s, 3H), 5.13 (s,2H), 7.22-7.30 (m, 3H), 7.31-7.37 (m, 1H), 7.38-7.41 (m, 1H), 7.57-7.61(m, 1H), 8.45 (s, 1H), 12.72 (br.s, 1H).

Example 1251-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[3-fluoro-2-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 170 mg (0.33 mmol) of ethyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[3-fluoro-2-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 5, 141 mg (87% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=0.98 min; m/z=493 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.34 (s, 3H), 3.37 (s, 3H), 5.22 (s,2H), 7.19-7.30 (m, 3H), 7.36-7.45 (m, 2H), 7.63-7.71 (m, 1H), 8.47 (s,1H), 12.71 (br.s, 1H).

Example 1261-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-fluoro-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 161 mg (0.31 mmol) of ethyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-fluoro-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 4, 115 mg (76% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=0.98 min; m/z=493 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.34 (s, 3H), 3.36-3.39 (m, 3H), 5.17(s, 2H), 7.21-7.29 (m, 2H), 7.38 (s, 2H), 7.65-7.74 (m, 2H), 8.42 (s,1H), 12.72 (br.s, 1H).

Example 1273-(2-chloro-3,6-difluorobenzyl)-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121, with reaction time 30 min. Proceeding from 110 mg (0.22mmol) of ethyl3-(2-chloro-3,6-difluorobenzyl)-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 6, 80 mg (76% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=0.93 min; m/z=477 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.2-3.4 (2 s, concealed by watersignal), 5.24 (s, 2H), 7.14-7.19 (m, 1H), 7.23-7.32 (m, 2H), 7.32-7.36(m, 1H), 7.40-7.48 (m, 1H), 8.39 (s, 1H), 12.74 (br.s, 1H).

Example 1283-(3-chloro-2-methylbenzyl)-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121, with a reaction time of 30 min. Proceeding from 75 mg(0.16 mmol) of ethyl3-(3-chloro-2-methylbenzyl)-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 7, 62 mg (87% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=0.96 min; m/z=455 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.41 (s, 3H), 3.34 (s, 3H), 3.37 (s,3H), 5.08 (s, 2H), 7.06-7.09 (m, 1H), 7.17 (t, 1H), 7.22-7.29 (m, 2H),7.33-7.37 (m, 1H), 7.39-7.42 (m, 1H), 8.44 (s, 1H), 12.73 (br.s, 1H).

Example 1293-(3-chloro-5-fluorobenzyl)-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were analogous toExample 121. The reaction time was 45 min. Proceeding from 244 mg (0.50mmol) of ethyl3-(3-chloro-5-fluorobenzyl)-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 9, 198 mg (85% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=0.98 min; m/z=459 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.31 (s, 3H), 3.37 (s, 3H), 5.02-5.09(m, 2H), 7.19-7.33 (m, 4H), 7.33-7.38 (m, 1H), 7.39 (s, 1H), 8.39 (s,1H), 12.73 (s, 1H).

Example 1301-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[3-fluoro-5-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were analogous toExample 121. The reaction time was 45 min. Proceeding from 268 mg (0.51mmol) of ethyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[3-fluoro-5-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 10, 215 mg (84% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.00 min; m/z=493 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.31 (s, 3H), 3.37 (s, 3H), 5.15 (s,2H), 7.23 (dd, 1H), 7.28 (d, 1H), 7.38 (d, 1H), 7.54 (d, 1H), 7.58-7.65(m, 2H), 8.40 (s, 1H), 12.73 (s, 1H).

Example 1311-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (racemate)

103 mg (0.19 mmol) of ethyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 11 were initially charged in acetonitrile/water 1.5:1 (2.5ml), 36 mg (0.43 mmol) of sodium hydrogencarbonate were added and themixture was stirred at 80° C. for 4 h. The cooled reaction mixture wasacidified with 1N hydrochloric acid and extracted twice with ethylacetate, and the combined organic phases were dried over magnesiumsulphate, filtered and concentrated. The residue was separated by meansof HPLC (Method 7). The product fractions were almost completelyconcentrated on a rotary evaporator, and the precipitated solid wasfiltered off and dried at the high-vacuum pump. This gave 32 mg (33% oftheory) of the title compound.

LC-MS (Method 1): R_(t)=1.01 min; m/z=501 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.39-2.46 (m, 1H), 2.46-2.48 (m, 1H,partly concealed by DMSO signal), 3.04-3.16 (m, 1H), 3.23-3.29 (m, 1H,partly concealed by water signal), 3.31 (s, 3H), 3.35-3.38 (m, 3H),6.36-6.60 (m, 1H), 7.13-7.29 (m, 2H), 7.31-7.42 (m, 2H), 7.49-7.57 (m,2H), 8.38 (s, 1H), 12.70 (br.s, 1H).

Example 1321-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (R enantiomer)

4.20 g (7.79 mmol) of ethyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 13 were stirred with 40 ml of glacial acetic acid and 20 mlof conc. hydrochloric acid at reflux temperature for 1 h. The reactionmixture was cooled to RT, then diluted with 300 ml of water. Theprecipitated solid was filtered off with suction, washed with a littlewater and dried under HV. The solid thus obtained was stirred with 45 mlof toluene. At first it dissolved completely, but after a few minutes acrystalline solid formed. The mixture was cooled to 0° C. and stirred atthis temperature for 30 min. Subsequently, the solid was filtered off,washed with 5 ml of toluene and dried under HV. This gave 3.17 g (81% oftheory) of the title compound.

LC-MS (Method 1): R_(t)=1.06 min; m/z=501 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.38-2.46 (m, 1H), 2.46-2.60 (m, 1Hpartly hidden under DMSO signal), 3.10 (dt, 1H), 3.23-3.35 (m, 1H partlyhidden under DMSO signal), 3.31 (s, 4H), 3.36 (s, 3H), 6.36-6.60 (m,1H), 7.12-7.30 (m, 2H), 7.31-7.43 (m, 2H), 7.48-7.58 (m, 2H), 8.38 (s,1H), 12.71 (br.s, 1H).

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=2.42-2.53 (m, 1H), 2.60-2.72 (m, 1H),3.11-3.25 (m, 1H), 3.39 (s, 3H), 3.41 (s, 3H), 3.45-3.55 (m, 1H),6.59-6.71 (m, 1H), 6.94 (br. s, 1H), 7.04 (s, 2H), 7.28-7.41 (m, 2H),7.54 (d, 1H), 8.57 (s, 1H), 12.45 (br. s, 1H).

In an analogous experiment, it was possible to isolate a fraction with99% purity. For this batch, the specific optical rotation measured was:

Specific optical rotation: α_(D) ²⁰=+110.6°, (methanol, c=0.405 g/100ml).

An x-ray structure analysis in the complex with chymase confirmed the Rconfiguration for this enantiomer.

Example 1331-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[(1S)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (S enantiomer)

5.10 g (9.65 mmol) of the compound from Example 12 were stirred in 50 mlof glacial acetic acid and 25 ml of conc. hydrochloric acid at refluxtemperature for 15 min. After cooling to RT, the mixture was dilutedwith 5 ml of acetonitrile and separated in portions by preparative HPLC(Method 7). This gave 4.5 g (93% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.02 min; m/z=501 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=2.33-2.46 (m, 1H), 2.58 (dtd, 1H),3.04-3.16 (m, 1H), 3.30 (s, 3H), 3.33 (s, 3H), 3.36-3.47 (m, 1H),6.50-6.66 (m, 1H), 6.86 (br.s, 1H), 6.95 (br. s, 2H), 7.20-7.33 (m, 2H),7.46 (d, 1H), 8.49 (s, 1H), 12.38 (br.s, 1H).

Example 1341-(6-fluoro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (R enantiomer)

The preparation and purification of the title compound were analogous toExample 121, with reaction time 45 min. Proceeding from 120 mg (0.22mmol) of ethyl1-(6-fluoro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 104, after additional purification by means of HPLC (Method8), 92 mg (80% of theory) of the title compound were obtained.

LC-MS (Method 5): R_(t)=1.09 min; m/z=519 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=2.31-2.43 (m, 1H), 2.51-2.62 (m, 1H),3.03-3.14 (m, 1H), 3.28 (s, 3H), 3.29 (s, 3H), 3.34-3.47 (m, 1H),6.50-6.58 (m, 1H), 6.76-6.84 (m, 2H), 7.21-7.27 (m, 2H), 7.41-7.47 (m,1H), 8.41 (s, 1H), 12.31 (s, 1H).

Example 1353-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 170 mg (0.30 mmol) of ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 21, 133 mg (82% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.20 min; m/z=537 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 6H), 3.82-3.96 (m, 4H), 5.18(s, 2H), 7.21-7.27 (m, 1H), 7.34 (d, 1H), 7.43-7.48 (m, 1H), 7.50-7.63(m, 2H), 7.77-7.84 (m, 1H), 8.50 (s, 1H), 12.71 (br.s, 1H).

Example 1361-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 170 mg (0.31 mmol) of ethyl1-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)-benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 22, 144 mg (89% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.10 min; m/z=517 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 6H), 2.47 (s, 3H), 3.84-3.95(m, 4H), 5.12 (s, 2H), 7.22-7.26 (m, 1H), 7.33 (s, 3H), 7.46-7.48 (m,1H), 7.59-7.63 (m, 1H), 8.49 (s, 1H), 12.72 (br.s, 1H).

Example 1373-(2,3-dichlorobenzyl)-1-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 244 mg (0.46 mmol) of ethyl3-(2,3-dichlorobenzyl)-1-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 23, 188 mg (81% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.08 min; m/z=503 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 6H), 3.83-3.95 (m, 4H), 5.14(s, 2H), 7.21-7.27 (m, 2H), 7.31-7.37 (m, 2H), 7.45-7.47 (m, 1H),7.57-7.61 (m, 1H), 8.49 (s, 1H), 12.71 (br.s, 1H).

Example 1381-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[3-fluoro-2-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 167 mg (0.30 mmol) of ethyl1-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[3-fluoro-2-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 24, 96 mg (61% of theory) of the title compound wereobtained.

LC-MS (Method 3): R_(t)=1.24 min; m/z=521 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 6H), 3.83-3.96 (m, 4H), 5.23(s, 2H), 7.19-7.26 (m, 2H), 7.31-7.37 (m, 1H), 7.37-7.48 (m, 2H),7.63-7.72 (m, 1H), 8.50 (s, 1H), 12.71 (br.s, 1H).

Example 1393-[3-chloro-2-(trifluoromethyl)benzyl]-1-(3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 73 mg (0.13 mmol) of ethyl3-[3-chloro-2-(trifluoromethyl)benzyl]-1-(3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 18, 50 mg (69% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.08 min; m/z=523 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 3.37 (s, 3H), 3.88 (q,2H), 5.21-5.27 (m, 2H), 7.21-7.30 (m, 2H), 7.33-7.37 (m, 1H), 7.43-7.46(m, 1H), 7.58-7.68 (m, 2H), 8.49 (s, 1H), 12.72 (br.s, 1H).

Example 1403-[2-chloro-3-(trifluoromethyl)benzyl]-1-(3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 75 mg (0.14 mmol) of ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 19, 35 mg (49% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.02 min; m/z=523 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 3.37 (s, 3H), 3.88 (q,2H), 5.18 (s, 2H), 7.22-7.30 (m, 2H), 7.44-7.47 (m, 1H), 7.51-7.57 (m,1H), 7.58-7.62 (m, 1H), 7.79-7.83 (m, 1H), 8.49 (s, 1H), 12.73 (br.s,1H).

Example 1411-(3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)-benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 53 mg (0.10 mmol) of ethyl1-(3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 20, 23 mg (46% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.06 min; m/z=503 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 2.47 (s, 3H), 3.37 (s,3H), 3.87 (q, 2H), 5.11 (s, 2H), 7.22-7.30 (m, 2H), 7.33-7.43 (m, 2H),7.46-7.49 (m, 1H), 7.59-7.64 (m, 1H), 8.48 (s, 1H), 12.74 (br.s, 1H).

Example 1423-[3-chloro-2-(trifluoromethyl)benzyl]-1-[1-methyl-2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzimidazol-5-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 90 mg (0.15 mmol) of ethyl3-[3-chloro-2-(trifluoromethyl)benzyl]-1-[1-methyl-2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzimidazol-5-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 25, 55 mg (61% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.12 min; m/z=577 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.41 (s, 3H), 4.81 (q, 2H), 5.22-5.26(m, 2H), 7.30-7.39 (m, 3H), 7.51-7.55 (m, 1H), 7.57-7.67 (m, 2H), 8.46(s, 1H), 12.74 (br.s, 1H).

Example 1433-[2-chloro-3-(trifluoromethyl)benzyl]-1-[1-methyl-2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzimidazol-5-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 80 mg (0.13 mmol) of ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-[1-methyl-2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzimidazol-5-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 26, 46 mg (57% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.12 min; m/z=577 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.41 (s, 3H), 4.80 (q, 2H), 5.17 (s,2H), 7.31-7.38 (m, 2H), 7.50-7.56 (m, 2H), 7.59-7.63 (m, 1H), 7.79-7.83(m, 1H), 8.45 (s, 1H), 12.75 (br.s, 1H).

Example 1441-[1-methyl-2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzimidazol-5-yl]-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 41 mg (0.07 mmol) of ethyl1-[1-methyl-2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzimidazol-5-yl]-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 27, 25 mg (63% of theory) of the title compound wereobtained.

LC-MS (Method 3): R_(t)=1.33 min; m/z=557 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.47 (s, 3H), 3.41 (s, 3H), 4.80 (q,2H), 5.11 (s, 2H), 7.31-7.43 (m, 4H), 7.55 (s, 1H), 7.58-7.63 (m, 1H),8.43 (s, 1H), 12.76 (br.s, 1H).

Example 1453-[2-chloro-3-(trifluoromethyl)benzyl]-1-[3-(cyclopropylmethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121, proceeding from 65 mg (0.11 mmol) of ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-[3-(cyclopropylmethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 29. The resulting crude product was additionally purifiedby means of preparative HPLC (Method 22). This gave 23 mg (62% oftheory) of the title compound.

LC-MS (Method 1): R_(t)=1.08 min; m/z=549 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=0.35-0.49 (m, 4H), 1.14-1.26 (m, 1H),2.5 (s, concealed by DMSO signal), 3.38 (s, 3H), 3.72 (d, 2H), 5.18 (s,2H), 7.22-7.31 (m, 2H), 7.50-7.57 (m, 2H), 7.58-7.63 (m, 1H), 7.79-7.83(m, 1H), 8.48 (s, 1H), 12.73 (br.s, 1H).

Example 1461-[3-(cyclopropylmethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were analogous toExample 121. Proceeding from 69 mg (0.12 mmol) of ethyl1-[3-(cyclopropylmethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 30, after additional purification by means of preparativeHPLC (Method 10), 29 mg (90%, 40% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.08 min; m/z=529 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=0.35-0.41 (m, 2H), 0.42-0.49 (m, 2H),1.15-1.25 (m, 1H), 2.47 (s, 3H), 3.38 (s, concealed by DMSO signal),3.72 (d, 2H), 5.12 (s, 2H), 7.23-7.30 (m, 2H), 7.33-7.43 (m, 2H),7.51-7.54 (m, 1H), 7.59-7.63 (m, 1H), 8.47 (s, 1H), 12.73 (br.s, 1H).

Example 1473-[3-chloro-2-(trifluoromethyl)benzyl]-1-[3-(cyclopropylmethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 115 mg (0.23 mmol) of ethyl3-[3-chloro-2-(trifluoromethyl)benzyl]-1-[3-(cyclopropylmethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 31, 92 mg (84% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.13 min; m/z=549 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=0.35-0.41 (m, 2H), 0.41-0.49 (m, 2H),1.15-1.25 (m, 1H), 3.4 (s, concealed by water signal), 3.72 (d, 2H),5.25 (br.s, 2H), 7.22-7.31 (m, 2H), 7.32-7.38 (m, 1H), 7.49-7.52 (m,1H), 7.57-7.68 (m, 2H), 8.48 (s, 1H), 12.73 (br.s, 1H).

Example 1483-[2-chloro-3-(trifluoromethyl)benzyl]-1-[1-methyl-3-(oxetan-2-ylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (racemate)

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 56 mg (0.09 mmol) of ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-[1-methyl-3-(oxetan-2-ylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 32, 10 mg (18% of theory) of the title compound wereobtained.

LC-MS (Method 3): R_(t)=1.24 min; m/z=565 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.11-2.21 (m, 1H), 2.26-2.36 (m, 1H),3.36 (s, 3H), 3.72 (q, 1H), 3.84-3.91 (m, 1H), 3.93-3.99 (m, 1H),4.11-4.18 (m, 1H), 5.09-5.20 (m, 3H), 7.25-7.32 (m, 2H), 7.43-7.46 (m,1H), 7.50-7.57 (m, 1H), 7.60-7.65 (m, 1H), 7.78-7.84 (m, 1H), 8.48 (s,1H), 12.74 (br.s, 1H).

Example 1491-(3-cyclobutyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121, with reaction time 5.5 h at 60° C. Proceeding from 33 mg(0.06 mmol) of ethyl1-(3-cyclobutyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 33, 18 mg (57% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.10 min; m/z=529 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.73-1.90 (m, 2H), 2.21-2.31 (m, 2H),2.47 (s, partly concealed by DMSO signal), 2.75-2.87 (m, 2H), 3.34 (s,partly concealed by water signal), 4.78-4.89 (m, 1H), 5.12 (s, 2H),7.24-7.29 (m, 2H), 7.34-7.39 (m, 1H), 7.40-7.44 (m, 1H), 7.59-7.63 (m,1H), 7.64-7.67 (m, 1H), 8.49 (s, 1H), 12.73 (br.s, 1H).

Example 1501-(3-cyclopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121, with reaction time 2 h at 60° C. Proceeding from 141 mg(0.26 mmol) of ethyl1-(3-cyclopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 35, 107 mg (80% of theory) of the title compound wereobtained.

LC-MS (Method 5): R_(t)=1.07 min; m/z=515 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=0.86-0.92 (m, 2H), 0.99-1.05 (m, 2H),2.47 (s, partly concealed by DMSO signal), 2.88-2.95 (m, 1H), 3.31 (s,partly concealed by water signal), 5.11 (s, 2H), 7.25 (s, 2H), 7.33-7.39(m, 1H), 7.40-7.47 (m, 2H), 7.59-7.63 (m, 1H), 8.45 (s, 1H), 12.72(br.s, 1H).

Example 1511-(3-isopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121, with reaction time 5.5 h at 60° C. Proceeding from 33 mg(0.06 mmol) of ethyl1-(3-isopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 34, 25 mg (76% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.06 min; m/z=517 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.44 (d, 6H), 2.47 (s, partlyconcealed by DMSO signal), 3.35 (s, partly concealed by water signal),4.55-4.64 (m, 1H), 5.12 (s, 2H), 7.21-7.28 (m, 2H), 7.33-7.43 (m, 2H),7.58-7.63 (m, 2H), 8.47 (s, 1H), 12.73 (br.s, 1H).

Example 1521-[3-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzimidazol-5-yl]-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 57 mg (0.09 mmol) of ethyl1-[3-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzimidazol-5-yl]-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 38, 48 mg (83% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.08 min; m/z=557 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.47 (s, 3H), 3.37 (s, 3H), 4.85 (q,2H), 5.11 (s, 2H), 7.30 (dd, 1H), 7.33-7.45 (m, 3H), 7.47-7.50 (m, 1H),7.59-7.63 (m, 1H), 8.49 (s, 1H), 12.73 (br.s, 1H).

Example 1531-[1-(cyclopropylmethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were analogous toExample 121. Proceeding from 52 mg (0.09 mmol) of ethyl1-[1-(cyclopropylmethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 39, after purification by means of HPLC (Method 8) andadditional fine purification of the compound by means of HPLC (Method23), 19 mg (37% of theory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.09 min; m/z=529 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=0.36-0.42 (m, 2H), 0.44-0.50 (m, 2H),1.15-1.25 (m, 1H), 2.47 (s, 3H), 3.35 (br.s, 3H, partly concealed bywater signal), 3.77 (d, 2H), 5.11 (s, 2H), 7.24 (dd, 1H), 7.33-7.43 (m,4H), 7.61 (d, 1H), 8.47 (s, 1H), 12.72 (s, 1H).

Example 1543-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-methyl-1H-benzotriazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 149 mg (0.29 mmol) of ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-methyl-1H-benzotriazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 71, 115 mg (80% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.03 min; m/z=480 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=4.37 (s, 3H), 5.19 (s, 2H), 7.51-7.58(m, 1H), 7.62-7.67 (m, 1H), 7.73 (dd, 1H), 7.79-7.84 (m, 1H), 8.00 (d,1H), 8.30-8.33 (m, 1H), 8.62 (s, 1H), 12.76 (br.s, 1H).

Example 155 1-(1-methyl-1H-benzotriazol-5 yl)-3-[2-methyl-3(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 151 mg (0.31 mmol) of ethyl1-(1-methyl-1H-benzotriazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 72, 124 mg (86% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.02 min; m/z=460 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.47 (s, 3H), 4.37 (s, 3H), 5.12 (s,2H), 7.33-7.40 (m, 1H), 7.42-7.48 (m, 1H), 7.59-7.64 (m, 1H), 7.70-7.76(m, 1H), 8.00 (d, 1H), 8.31-8.35 (m, 1H), 8.61 (s, 1H), 12.75 (br.s,1H).

Example 1563-(2,3-dichlorobenzyl)-1-(1-methyl-1H-benzotriazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 188 mg (0.40 mmol) of ethyl3-(2,3-dichlorobenzyl)-1-(1-methyl-1H-benzotriazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 73, 143 mg (80% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.00 min; m/z=446 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=4.37 (s, 3H), 5.14 (s, 2H), 7.27-7.31(m, 1H), 7.32-7.38 (m, 1H), 7.56-7.62 (m, 1H), 7.70-7.74 (m, 1H), 8.00(d, 1H), 8.30-8.33 (m, 1H), 8.61 (s, 1H), 12.75 (br.s, 1H).

Example 1573-[3-chloro-2-(trifluoromethyl)benzyl]-1-(1-methyl-1H-benzotriazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 115 mg (0.31 mmol) of ethyl3-[3-chloro-2-(trifluoromethyl)benzyl]-1-(1-methyl-1H-benzotriazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 74, 92 mg (84% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.03 min; m/z=480 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=4.37 (s, 3H), 5.22-5.28 (m, 2H),7.37-7.42 (m, 1H), 7.58-7.68 (m, 2H), 7.69-7.74 (m, 1H), 8.00 (d, 1H),8.29-8.33 (m, 1H), 8.63 (s, 1H), 12.75 (br.s, 1H).

Example 1581-(1-methyl-1H-indazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxlicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 254 mg (0.52 mmol) of ethyl1-(1-methyl-1H-indazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 75, 212 mg (88% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.04 min; m/z=459 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.47 (s, 3H), 4.10 (s, 3H), 5.12 (s,2H), 7.33-7.39 (m, 1H), 7.41-7.46 (m, 1H), 7.52-7.56 (m, 1H), 7.59-7.63(m, 1H), 7.76-7.80 (m, 1H), 7.97-7.99 (m, 1H), 8.16-8.19 (m, 1H), 8.52(s, 1H), 12.72 (br.s, 1H).

Example 1593-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-methyl-1H-benzimidazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

94 mg (0.18 mmol) of ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-methyl-1H-benzimidazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 82 in 1.5 ml of glacial acetic acid/conc. hydrochloric acid2:1 (v/v) were heated to 120° C. for 30 min. The cooled reaction mixturewas admixed with water and extracted twice with dichloromethane, and thecombined organic phases were dried over magnesium sulphate andconcentrated. The residue was stirred with ethyl acetate, and theprecipitated solid was filtered off with suction and dried at 50° C.under reduced pressure. This gave 88 mg (98% of theory) of the titlecompound.

LC-MS (Method 3): R_(t)=1.12 min; m/z=479 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=4.00 (s, 3H), 5.19 (s, 2H), 7.54 (t,1H), 7.59-7.67 (m, 2H), 7.81 (d, 1H), 7.92 (d, 1H), 8.10 (s, 1H), 8.56(s, 1H), 9.13 (s, 1H).

Example 1601-(1-methyl-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 170 mg (0.35 mmol) of ethyl1-(1-methyl-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 77, 124 mg (77% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=0.90 min; m/z=459 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.47 (s, 3H), 3.89 (s, 3H), 5.12 (s,2H), 7.33-7.40 (m, 1H), 7.41-7.46 (m, 2H), 7.59-7.63 (m, 1H), 7.71 (d,1H), 7.86-7.89 (m, 1H), 8.33 (s, 1H), 8.50 (s, 1H), 12.72 (br.s, 1H).

Example 1613-[3-chloro-2-(trifluoromethyl)benzyl]-1-(1-methyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 82 mg (0.16 mmol) of ethyl3-[3-chloro-2-(trifluoromethyl)benzyl]-1-(1-methyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 78, 52 mg (66% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=0.93 min; m/z=479 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.89 (s, 3H), 5.25 (br.s, 2H),7.35-7.46 (m, 2H), 7.58-7.68 (m, 2H), 7.71 (d, 1H), 7.84-7.88 (m, 1H),8.33 (s, 1H), 8.51 (s, 1H), 12.70 (br.s, 1H).

Example 1623-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-methyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 120 mg (0.16 mmol) of ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-methyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 79, 83 mg (74% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=0.89 min; m/z=479 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.89 (s, 3H), 5.18 (s, 2H), 7.42-7.47(m, 1H), 7.51-7.57 (m, 1H), 7.61-7.65 (m, 1H), 7.71 (d, 1H), 7.79-7.83(m, 1H), 7.86-7.89 (m, 1H), 8.33 (s, 1H), 8.51 (s, 1H), 12.70 (br.s,1H).

Example 1631-(2-carbamoyl-1-methyl-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121, with a reaction time of 3.5 h at 60° C. Proceeding from116 mg (0.21 mmol) of ethyl1-(2-carbamoyl-1-methyl-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 81, after additional purification by means of preparativeHPLC (Method 9), 40 mg (36% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=0.96 min; m/z=502 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.47 (s, partly concealed by DMSOsignal), 4.16 (s, 3H), 5.13 (s, 2H), 7.34-7.40 (m, 1H), 7.42-7.47 (m,1H), 7.54-7.58 (m, 1H), 7.59-7.64 (m, 1H), 7.83 (d, 1H), 7.90-7.94 (m,1H), 7.96-7.99 (m, 1H), 8.30-8.35 (m, 1H), 8.53 (s, 1H), 12.73 (br.s,1H).

Example 1641-(1-ethyl-2-methyl-1H-benzimidazol-5-yl)-3-[3-fluoro-2-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

153 mg (0.30 mmol) of ethyl1-(1-ethyl-2-methyl-1H-benzimidazol-5-yl)-3-[3-fluoro-2-(trifluoromethyl)-benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 83 were initially charged in 2.1 ml of glacial acetic acidand 1.1 ml of conc. hydrochloric acid and stirred at 120° C. for 1 h.Subsequently, the mixture cooled to RT was admixed with water andextracted three times with dichloromethane. The combined organic phaseswere dried over magnesium sulphate, filtered and concentrated. In orderto remove residues of acetic acid, the residue was stirred withmethanol/dichloromethane, concentrated again and dried under reducedpressure. This gave 120 mg (81% of theory) of the title compound.

LC-MS (Method 3): R_(t)=1.02 min; m/z=491 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.36 (t, 3H), 2.72 (s, 3H), 4.38 (q,2H), 5.23 (s, 2H), 7.23-7.28 (m, 1H), 7.38-7.45 (m, 1H), 7.51-7.57 (m,1H), 7.64-7.71 (m, 1H), 7.86-7.93 (m, 2H), 8.54 (s, 1H), 12.71 (br.s,1H).

Example 1651-(1-ethyl-1H-benzimidazol-5-yl)-3-[3-fluoro-2-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 73 mg (0.15 mmol) of ethyl1-(1-ethyl-1H-benzimidazol-5-yl)-3-[3-fluoro-2-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 90, 16 mg (23% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=0.89 min; m/z=477 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.43 (t, 3H), 4.33 (q, 2H), 5.23 (s,2H), 7.21-7.27 (m, 1H), 7.37-7.45 (m, 2H), 7.63-7.71 (m, 1H), 7.76 (d,1H), 7.84-7.88 (m, 1H), 8.40 (s, 1H), 8.49 (s, 1H), 12.70 (br.s, 1H).

Example 1663-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-ethyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

53 mg (0.10 mmol) of ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-ethyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 91 were initially charged in 0.7 ml of glacial acetic acidand 0.4 ml of conc. hydrochloric acid and stirred at 120° C. for 1 h.Subsequently, the mixture cooled to RT was admixed with water andextracted three times with dichloromethane. The combined organic phaseswere dried over magnesium sulphate, filtered and concentrated. Theresidue was purified by means of preparative HPLC (Method 8). This gave37 mg (75% of theory) of the title compound.

LC-MS (Method 1): R_(t)=0.94 min; m/z=493 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.43 (t, 3H), 4.33 (q, 2H), 5.18 (s,2H), 7.40-7.45 (m, 1H), 7.51-7.57 (m, 1H), 7.60-7.64 (m, 1H), 7.76 (d,1H), 7.79-7.83 (m, 1H), 7.86-7.88 (m, 1H), 8.40 (s, 1H), 8.48 (s, 1H).

Example 1671-(1-ethyl-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 166. Proceeding from 38 mg (0.08 mmol) of ethyl1-(1-ethyl-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 80, 9 mg (25% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=0.94 min; m/z=473 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.43 (t, 3H), 2.47 (s, 3H), 4.33 (q,2H), 5.12 (s, 2H), 7.33-7.39 (m, 1H), 7.40-7.45 (m, 2H), 7.59-7.63 (m,1H), 7.76 (d, 1H), 7.86-7.88 (m, 1H), 8.40 (s, 1H), 8.46 (s, 1H).

Example 1683-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-ethyl-2-methyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 166. Proceeding from 114 mg (0.21 mmol) of ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-ethyl-2-methyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 84, 93 mg (83% of theory) of the title compound wereobtained.

LC-MS (Method 3): R_(t)=1.09 min; m/z=507 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.34 (t, 3H), 2.66 (s, 3H), 4.33 (q,2H), 5.18 (s, 2H), 7.43-7.49 (m, 1H), 7.51-7.57 (m, 1H), 7.61-7.65 (m,1H), 7.76-7.85 (m, 3H), 8.51 (s, 1H), 12.70 (br.s, 1H).

Example 1691-(1-cyclohexyl-2-methyl-1H-benzimidazol-5-yl)-3-[3-fluoro-2-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 166. Proceeding from 90 mg (0.15 mmol) of ethyl1-(1-cyclohexyl-2-methyl-1H-benzimidazol-5-yl)-3-[3-fluoro-2-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 85, 74 mg (81% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.01 min; m/z=545 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.38-1.57 (m, 3H), 1.67-1.74 (m, 1H),1.84-1.94 (m, 4H), 2.12-2.25 (m, 2H), 2.68 (s, 3H), 4.33-4.43 (m, 1H),5.23 (s, 2H), 7.25 (d, 1H), 7.36-7.46 (m, 2H), 7.64-7.71 (m, 1H),7.77-7.82 (m, 1H), 7.92-8.01 (m, 1H), 8.51 (s, 1H), 12.70 (br.s, 1H).

Example 1701-(1-isopropyl-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

91 mg (0.18 mmol) of ethyl1-(1-isopropyl-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 93 were initially charged in 1.3 ml of glacial acetic acidand 0.6 ml of conc. hydrochloric acid and stirred at 120° C. for 1 h.Subsequently, the mixture cooled to RT was admixed with water andextracted three times with dichloromethane. The combined organic phaseswere dried over magnesium sulphate, filtered and concentrated. Theresidue was stirred with methanol, and the solid was filtered off anddried under reduced pressure. The filtrate was concentrated again andthe residue was dried under reduced pressure. This gave a total of 61 mg(70% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.01 min; m/z=487 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.56 (d, 6H), 2.47 (s, 3H), 4.78-4.87(m, 1H), 5.12 (s, 2H), 7.33-7.39 (m, 1H), 7.40-7.46 (m, 2H), 7.59-7.63(m, 1H), 7.80 (d, 1H), 7.87-7.90 (m, 1H), 8.48-8.52 (m, 2H), 12.71(br.s, 1H).

Example 1713-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-isopropyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

65 mg (0.12 mmol) of ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-isopropyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 86 were initially charged in 0.9 ml of glacial acetic acidand 0.4 ml of conc. hydrochloric acid and stirred at 120° C. for 1 h.Subsequently, the mixture cooled to RT was admixed with water andextracted three times with dichloromethane. The combined organic phaseswere dried over magnesium sulphate, filtered and concentrated. Theresidue was stirred with methanol, and the solid was filtered off,washed with methanol and dried under reduced pressure. The filtrate wasconcentrated and the residue was dried under reduced pressure. This gavea total of 44 mg (71% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.01 min; m/z=507 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.55 (s, 3H), 1.57 (s, 3H), 4.78-4.87(m, 1H), 5.18 (s, 2H), 7.39-7.45 (m, 1H), 7.51-7.57 (m, 1H), 7.61-7.66(m, 1H), 7.78-7.83 (m, 2H), 7.86-7.89 (m, 1H), 8.50 (s, 1H), 8.52 (s,1H), 12.70 (br.s, 1H).

Example 1723-(2,3-dichlorobenzyl)-1-(1-isopropyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 171. Proceeding from 83 mg (0.17 mmol) of ethyl3-(2,3-dichlorobenzyl)-1-(1-isopropyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 87, 59 mg (72% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=0.99 min; m/z=473 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.56 (d, 6H), 4.78-4.86 (m, 1H), 5.14(s, 2H), 7.26-7.30 (m, 1H), 7.32-7.38 (m, 1H), 7.40-7.44 (m, 1H),7.57-7.61 (m, 1H), 7.80 (d, 1H), 7.86-7.89 (m, 1H), 8.48-8.52 (m, 2H),12.70 (br.s, 1H).

Example 1733-[3-chloro-2-(trifluoromethyl)benzyl]-1-[1-(cyclopropylmethyl)-1H-benzimidazol-5-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 171. Proceeding from 135 mg (0.24 mmol) of ethyl3-[3-chloro-2-(trifluoromethyl)benzyl]-1-[1-(cyclopropylmethyl)-1H-benzimidazol-5-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 92, 59 mg (45% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.00 min; m/z=519 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=0.41-0.48 (m, 2H), 0.52-0.58 (m, 2H),1.27-1.36 (m, 1H), 4.17 (d, 2H), 5.25 (s, 2H), 7.36-7.44 (m, 2H),7.58-7.68 (m, 2H), 7.81 (d, 1H), 7.85-7.89 (m, 1H), 8.43 (s, 1H), 8.53(s, 1H), 12.70 (br.s, 1H).

Example 1743-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-cyclobutyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 171. Proceeding from 153 mg (0.25 mmol) of ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-cyclobutyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 88, 90 mg (68% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.02 min; m/z=519 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.86-1.96 (m, 2H), 2.5-2.6 (m, partlyconcealed by DMSO signal), 4.99-5.09 (m, 1H), 5.18 (s, 2H), 7.40-7.45(m, 1H), 7.50-7.57 (m, 1H), 7.60-7.66 (m, 1H), 7.75 (d, 1H), 7.79-7.83(m, 1H), 7.87-7.90 (m, 1H), 8.51 (s, 1H), 8.55 (s, 1H), 12.71 (br.s,1H).

Example 1753-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-methyl-1H-indazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 228 mg (0.45 mmol) of ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-methyl-1H-indazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 89, 170 mg (77% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.04 min; m/z=479 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=4.10 (s, 3H), 5.18 (s, 2H), 7.51-7.57(m, 2H), 7.61-7.66 (m, 1H), 7.76-7.83 (m, 2H), 7.96-7.99 (m, 1H), 8.18(s, 1H), 8.54 (s, 1H), 12.71 (br.s, 1H).

Example 1761-(1-methyl-1H-indazol-5-yl)-2,4-dioxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (R enantiomer)

The preparation and purification of the title compound were analogous toExample 121, with reaction time 45 min. Proceeding from 119 mg (0.24mmol) of ethyl1-(1-methyl-1H-indazol-5-yl)-2,4-dioxo-3-[4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 76, 81 mg (71% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.08 min; m/z=471 (M+H)⁺.

¹H NMR (400 MHz, CDCl₃): δ [ppm]=2.45-2.54 (m, 1H), 2.65-2.72 (m, 1H),3.13-3.24 (m, 1H), 3.48-3.61 (m, 1H), 4.12 (s, 3H), 6.62-6.71 (m, 1H),7.28-7.35 (m, 3H), 7.48-7.56 (m, 2H), 7.70 (s, 1H), 8.06 (s, 1H), 8.63(s, 1H), 12.53 (s, 1H).

Example 1771-(1,3-dimethyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 195 mg (0.35 mmol) of ethyl1-(1,3-dimethyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 94, 153 mg (79% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.11 min; m/z=525 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.47 (s, 3H), 3.26 (s, 3H), 3.30 (s,partly concealed by water signal), 5.10 (s, 2H), 7.13-7.17 (m, 1H),7.20-7.24 (m, 1H), 7.26-7.30 (m, 1H), 7.32-7.42 (m, 2H), 7.59-7.63 (m,1H), 8.48 (s, 1H), 12.74 (br.s, 1H).

Example 1783-[3-chloro-2-(trifluoromethyl)benzyl]-1-(1,3-dimethyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 120 mg (0.21 mmol) of ethyl3-[3-chloro-2-(trifluoromethyl)benzyl]-1-(1,3-dimethyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 95, 98 mg (85% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.11 min; m/z=545 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.27 (s, partly concealed by DMSOsignal), 3.30 (s, 3H), 5.23 (s, 2H), 7.13-7.18 (m, 1H), 7.18-7.23 (m,1H), 7.24-7.27 (m, 1H), 7.31-7.36 (m, 1H), 7.56-7.67 (m, 2H), 8.50 (s,1H), 12.73 (br.s, 1H).

Example 1793-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1,3-dimethyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 167 mg (0.29 mmol) of ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1,3-dimethyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 96, 129 mg (80% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.12 min; m/z=545 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.27 (s, 3H), 3.30 (s, 3H), 5.17 (s,2H), 7.13-7.18 (m, 1H), 7.20-7.24 (m, 1H), 7.25-7.28 (m, 1H), 7.50-7.56(m, 1H), 7.56-7.61 (m, 1H), 7.79-7.83 (m, 1H), 8.49 (s, 1H), 12.74(br.s, 1H).

Example 1801-(1,3-dimethyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl)-2,4-dioxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (R enantiomer)

The preparation and purification of the title compound were analogous toExample 121. Proceeding from 130 mg (0.23 mmol) of ethyl1-(1,3-dimethyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl)-2,4-dioxo-3-[4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 97, after additional purification by means of preparativeHPLC (Method 8), 50 mg (40% of theory) of the title compound wereobtained.

LC-MS (Method 4): R_(t)=2.44 min; m/z=537 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=2.32-2.44 (m, 1H), 2.51-2.63 (m, 1H),3.04-3.16 (m, 1H), 3.20 (s, 3H), 3.23 (s, 3H), 3.36-3.47 (m, 1H),6.51-6.60 (m, 1H), 6.65 (s, 1H), 6.75 (d, 1H), 6.89 (d, 1H), 7.21-7.30(m, 2H), 7.42-7.49 (m, 1H), 8.44 (s, 1H).

Example 1813-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 20 mg (0.04 mmol) of ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 16, 14 mg (71% of theory) of the title compound wereobtained.

LC-MS (Method 3): R_(t)=1.16 min; m/z=495 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.30 (s, 3H), 5.16 (s, 2H), 7.17-7.23(m, 3H), 7.49-7.55 (m, 1H), 7.60-7.64 (m, 1H), 7.78-7.83 (m, 1H), 8.44(s, 1H), 11.14 (s, 1H), 12.69 (br.s, 1H).

Example 1821-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 129 mg (0.26 mmol) of ethyl1-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)-benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 14, 113 mg (93% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=0.94 min; m/z=475 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.46 (s, 3H), 3.32 (s, 3H), 5.10 (s,2H), 7.17-7.23 (m, 3H), 7.32-7.38 (m, 1H), 7.40-7.45 (m, 1H), 7.58-7.63(m, 1H), 8.43 (s, 1H), 11.14 (s, 1H), 12.70 (br.s, 1H).

Example 1833-(2,3-dichlorobenzyl)-1-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 30 mg (0.06 mmol) of ethyl3-(2,3-dichlorobenzyl)-1-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 15, 22 mg (73% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=0.91 min; m/z=461 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.30 (s, partly concealed by watersignal), 5.12 (s, 2H), 7.20 (s, 3H), 7.25-7.29 (m, 1H), 7.30-7.36 (m,1H), 7.56-7.61 (m, 1H), 8.43 (s, 1H), 11.14 (s, 1H), 12.69 (br.s, 1H).

Example 184 ethyl1-(6-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification of the title compound were analogous toExample 1. Proceeding from 200 mg (0.60 mmol) of ethyl1-(6-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 27A and 168 mg (0.66 mmol) of1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene, after additionalrecrystallization from ethanol, 207 mg (62% of theory) of the titlecompound were obtained.

LC-MS (Method 1): R_(t)=0.98 min; m/z=503 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 2.09 (s, 3H), 2.45 (s,3H), 4.18 (q, 2H), 5.08 (d, 2H), 6.89 (s, 1H), 7.12 (s, 1H), 7.30-7.36(m, 2H), 7.57-7.62 (m, 1H), 8.37 (s, 1H), 10.80 (s, 1H).

Example 185 ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(6-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation of the title compound was analogous to Example 37.Proceeding from 200 mg (0.60 mmol) of ethyl1-(6-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 27A and 182 mg (0.66 mmol) of1-(bromomethyl)-2-chloro-3-(trifluoromethyl)-benzene, after purificationby means of preparative HPLC (Method 8), 178 mg (56% of theory) of thetitle compound were obtained.

LC-MS (Method 1): R_(t)=1.01 min; m/z=523 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23 (t, 3H), 2.10 (s, 3H), 4.19 (q,2H), 5.15 (s, 2H), 6.89 (s, 1H), 7.11 (s, 1H), 7.49-7.57 (m, 2H),7.77-7.83 (m, 1H), 8.39 (s, 1H), 10.80 (s, 2H).

Example 1863-[2-chloro-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were analogous toExample 121, with a reaction time of 1 h. Proceeding from 99 mg (0.19mmol) of ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 37, 79 mg (85% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=0.89 min; m/z=481 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=5.16 (s, 2H), 7.00-7.04 (m, 1H),7.07-7.11 (m, 1H), 7.13-7.16 (m, 1H), 7.49-7.55 (m, 1H), 7.59-7.64 (m,1H), 7.78-7.83 (m, 1H), 8.43 (s, 1H), 10.87-10.92 (m, 2H), 12.68 (br.s,1H).

Example 1871-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were analogous toExample 121, with a reaction time of 1 h. Proceeding from 280 mg (0.55mmol) of ethyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 40, 186 mg (69% of theory) of the title compound wereobtained.

LC-MS (Method 5): R_(t)=1.06 min; m/z=476 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.47 (s, 3H), 3.38 (s, 3H), 5.10 (s,2H), 7.32-7.47 (m, 4H), 7.58-7.66 (m, 2H), 8.47 (s, 1H), 12.74 (br.s,1H).

Example 1883-[2-chloro-3-(trifluoromethyl)benzyl]-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were analogous toExample 121, with a reaction time of 1 h. Proceeding from 250 mg (0.47mmol) of ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 41, 220 mg (91% of theory) of the title compound wereobtained.

LC-MS (Method 5): R_(t)=1.07 min; m/z=496 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.38 (s, 3H), 5.16 (s, 2H), 7.38-7.47(m, 2H), 7.50-7.56 (m, 1H), 7.58-7.64 (m, 2H), 7.78-7.83 (m, 1H), 8.48(s, 1H), 12.74 (br.s, 1H).

Example 1891-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (R enantiomer)

3.40 g (6.60 mmol) of the compound from Example 42 in 44 ml of glacialacetic acid and 22 ml of concentrated hydrochloric acid were stirred atreflux temperature for 1 h. After cooling slightly (about 60° C.), themixture was fully concentrated under reduced pressure. The amorphousresidue was admixed with 50 ml of isopropanol and heated to reflux for15 min, in the course of which a solid formed. The suspension was thencooled to 10° C. and then the solid was filtered off with suction. Thesolid was washed twice with 15 ml each time of isopropanol, filtered offwith suction and dried under HV. This gave 2.53 g (79% of theory) of thetitle compound.

LC-MS (Method 1): R_(t)=1.12 min; m/z=488 (M+H)⁺.

Chiral analytical HPLC (Method 14): R_(t)=13.3 min; about 99% ee

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=2.40-2.52 (m, 1H), 2.59-2.72 (m, 1H),3.12-3.25 (m, 1H), 3.41 (s, 3H), 3.44-3.56 (m, 1H), 6.58-6.69 (m, 1H),7.04-7.11 (m, 1H), 7.15-7.21 (m, 1H), 7.24 (br.s, 1H), 7.29-7.38 (m,2H), 7.53 (s, 1H), 8.54 (s, 1H), 12.39 (br. s, 1H).

Specific rotation α_(D) ²⁰=+135.3° (methanol, c=0.43).

In an analogous experiment, the specific rotation of the product wasmeasured in chloroform: α_(D) ²⁰=+159.5° (chloroform, c=0.395).

An x-ray structure analysis in the complex with chymase confirmed the Rconfiguration for this enantiomer.

Example 1901-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-3-[(1S)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (S enantiomer)

420 mg (0.80 mmol) of the compound from Example 43 in 7.7 ml of glacialacetic acid/conc. hydrochloric acid 2:1 (v/v) were heated to reflux for1 h. Subsequently, the reaction mixture was concentrated on a rotaryevaporator and the residue was dried under HV. This gave 390 mg (96% oftheory) of the title compound.

LC-MS (Method 1): R_(t)=1.09 min; m/z=488 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=2.37-2.53 (m, 1H), 2.66 (dtd, 1H),3.10-3.26 (m, 1H), 3.41 (s, 3H), 3.44-3.55 (m, 1H), 6.58-6.71 (m, 1H),7.08 (d, 1H), 7.19 (br. d, 1H), 7.24 (br. s, 1H), 7.30-7.38 (m, 2H),7.50-7.59 (m, 1H), 8.55 (s, 1H).

Chiral analytical HPLC (Method 14): R_(t)=9.97 min, about 95% ee.

Specific rotation: α_(D) ²⁰=−122.5° (c=0.5, methanol).

Example 1913-(2,3-dichlorobenzyl)-1-(3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 210 mg (0.42 mmol) of ethyl3-(2,3-dichlorobenzyl)-1-(3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 45, 180 mg (89% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.08 min; m/z=476 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.28 (t, 3H), 3.90 (q, 2H), 5.12 (s,2H), 7.23-7.28 (m, 1H), 7.31-7.36 (m, 1H), 7.47 (s, 2H), 7.57-7.61 (m,1H), 7.62-7.65 (m, 1H), 8.48 (s, 1H), 12.70 (br.s, 1H).

Example 1921-(3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 185 mg (0.36 mmol) of ethyl1-(3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 44, 159 mg (90% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.10 min; m/z=490 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.28 (t, 3H), 2.47 (s, 3H), 3.90 (q,2H), 5.10 (s, 2H), 7.32-7.38 (m, 1H), 7.39-7.50 (m, 3H), 7.59-7.63 (m,1H), 7.64-7.66 (m, 1H), 8.48 (s, 1H), 12.72 (br.s, 1H).

Example 1933-[2-chloro-3-(trifluoromethyl)benzyl]-1-(3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 200 mg (0.37 mmol) of ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 46, 165 mg (85% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.10 min; m/z=510 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.28 (d, 3H), 3.90 (q, 2H), 5.17 (s,2H), 7.42-7.56 (m, 3H), 7.58-7.65 (m, 2H), 7.78-7.83 (m, 1H), 8.49 (s,1H), 12.73 (br.s, 1H).

Example 1941-(3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-3-[3-fluoro-2-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 150 mg (0.29 mmol) of ethyl1-(3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-3-[3-fluoro-2-(trifluoromethyl)-benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 47, 105 mg (73% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.05 min; m/z=494 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.28 (t, 3H), 3.90 (q, 2H), 5.21 (s,2H), 7.19-7.25 (m, 1H), 7.38-7.51 (m, 3H), 7.61-7.70 (m, 2H), 8.50 (s,1H), 12.72 (br.s, 1H).

Example 1951-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 390 mg (0.75 mmol) of ethyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-3-[2-methyl-3-(trifluoromethyl)-benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 48, 314 mg (81% of theory) of the title compound wereobtained.

LC-MS (Method 3): R_(t)=1.33 min; m/z=492 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.47 (s, 3H), 3.45 (s, 3H), 5.10 (s,2H), 7.32-7.38 (m, 1H), 7.39-7.43 (m, 1H), 7.46 (d, 1H), 7.60 (s, 2H),7.89 (d, 1H), 8.52 (s, 1H), 12.73 (br.s, 1H).

Example 1963-[2-chloro-3-(trifluoromethyl)benzyl]-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 216 mg (0.40 mmol) of ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 49, 155 mg (72% of theory) of the title compound wereobtained.

LC-MS (Method 3): R_(t)=1.33 min; m/z=512 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.45 (s, 3H), 5.17 (s, 2H), 7.46 (d,1H), 7.49-7.64 (m, 3H), 7.78-7.84 (m, 1H), 7.89 (d, 1H), 8.53 (s, 1H),12.73 (br.s, 1H).

Example 1973-[3-fluoro-2-(trifluoromethyl)benzyl]-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 241 mg (0.46 mmol) of ethyl3-[3-fluoro-2-(trifluoromethyl)benzyl]-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 50, 180 mg (73% of theory) of the title compound wereobtained.

LC-MS (Method 3): R_(t)=1.27 min; m/z=496 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.45 (s, 3H), 5.21 (s, 2H), 7.19-7.25(m, 1H), 7.37-7.49 (m, 2H), 7.55-7.60 (m, 1H), 7.62-7.70 (m, 1H),7.86-7.90 (m, 1H), 8.53 (s, 1H), 12.73 (br.s, 1H).

Example 198 1-(1,3-benzothiazol-6-yl)-3-[2-methyl-3(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 204 mg (0.41 mmol) of ethyl1-(1,3-benzothiazol-6-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 98, 160 mg (82% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.07 min; m/z=462 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.47 (partly concealed by DMSOsignal), 5.12 (s, 2H), 7.33-7.39 (m, 1H), 7.42-7.47 (m, 1H), 7.58-7.64(m, 1H), 7.70-7.75 (m, 1H), 8.22 (d, 1H), 8.39-8.43 (m, 1H), 8.61 (s,1H), 9.54 (s, 1H), 12.75 (br.s, 1H).

Example 1991-[3-hydroxy-1-methyl-2-oxo-3-(trifluoromethyl)-2,3-dihydro-1H-indol-5-yl]-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (racemate)

The preparation and purification of the title compound were in analogyto Example 121, with a reaction time of 20 min. Proceeding from 74 mg(0.12 mmol) of ethyl1-[3-hydroxy-1-methyl-2-oxo-3-(trifluoromethyl)-2,3-dihydro-1H-indol-5-yl]-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 63, 37 mg (53% of theory) of the title compound wereobtained.

LC-MS (Method 5): R_(t)=1.09 min; m/z=558 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.46 (s, 3H), 3.22 (s, 3H), 5.10 (s,2H), 7.29 (d, 1H), 7.32-7.38 (m, 1H), 7.41-7.45 (m, 1H), 7.58-7.63 (m,1H), 7.66-7.73 (m, 2H), 7.92 (s, 1H), 8.44 (s, 1H), 12.74 (br. s, 1H).

Example 2001-[3-fluoro-1-methyl-2-oxo-3-(trifluoromethyl)-2,3-dihydro-1H-indol-5-yl]-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (racemate)

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 85 mg (0.14 mmol) of ethyl1-[3-fluoro-1-methyl-2-oxo-3-(trifluoromethyl)-2,3-dihydro-1H-indol-5-yl]-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 64, 66 mg (82% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.18 min; m/z=560 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.46 (s, partly concealed by DMSOsignal), 3.26 (s, partly concealed by water signal), 5.10 (s, 2H),7.31-7.38 (m, 1H), 7.39-7.45 (m, 2H), 7.60 (d, 1H), 7.82-7.88 (m, 1H),7.95 (s, 1H), 8.57 (s, 1H), 12.75 (br.s, 1H).

Example 2013-[2-chloro-3-(trifluoromethyl)benzyl]-1-(3-hydroxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (racemate)

The preparation and purification of the title compound were in analogyto Example 121, with a reaction time of 45 min. Proceeding from 124 mg(0.22 mmol) of ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(3-hydroxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 62, 54 mg (50% of theory) of the title compound wereobtained, as were 24 mg (22% of theory) of Example 202. Analytical datafor the title compound:

LC-MS (Method 1): R_(t)=0.95 min; m/z=524 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.41 (s, 3H), 3.14 (s, 3H), 5.16 (s,2H), 6.12 (s, 1H), 7.14 (d, 1H), 7.47-7.57 (m, 3H), 7.59-7.64 (m, 1H),7.78-7.83 (m, 1H), 8.42 (s, 1H), 12.73 (br. s, 1H).

Example 2021-(3-chloro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-3-[2-chloro-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The title compound (24 mg) was isolated in the synthesis of Example 201.

LC-MS (Method 1): R_(t)=1.09 min; m/z=542 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.87 (s, 3H), 3.22 (s, 3H), 5.17 (s,2H), 7.26 (d, 1H), 7.51-7.56 (m, 1H), 7.57-7.64 (m, 2H), 7.77-7.84 (m,2H), 8.48 (s, 1H), 12.75 (br. s, 1H).

Example 2033-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were analogous toExample 121, with a reaction time of 15 min. Proceeding from 265 mg(0.51 mmol) of ethyl1-(1-methyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 100, after purification by means of preparative HPLC(Method 8), 121 mg (46% of theory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.03 min; m/z=490 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.47 (s, 3H), 3.3 (concealed by watersignal), 5.10 (s, 2H), 5.30 (s, 2H), 7.21-7.26 (m, 1H), 7.31-7.43 (m,2H), 7.45-7.48 (m, 1H), 7.53-7.62 (m, 2H), 8.46 (s, 1H), 12.72 (br.s,1H).

Example 2041-(1-methyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-2,4-dioxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (R enantiomer)

The preparation and purification of the title compound were analogous toExample 121, with reaction time 45 min. Proceeding from 135 mg (0.25mmol) of ethyl1-(1-methyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-2,4-dioxo-3-[4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 101, 81 mg (59% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.04 min; m/z=502 (M+H)⁺.

¹H NMR (400 MHz, CDCl₃): δ [ppm]=2.39-2.52 (m, 1H), 2.64-2.71 (m, 1H),3.12-3.25 (m, 1H), 3.41 (s, 3H), 3.47-3.61 (m, 1H), 5.22 (s, 2H),6.60-6.70 (m, 1H), 7.05 (d, 1H), 7.15 (s, 1H), 7.28-7.36 (m, 3H),7.50-7.57 (m, 1H), 8.53 (s, 1H), 12.18-12.70 (m, 2H).

Example 2053-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121, with a reaction time of 45 min. Proceeding from 127 mg(0.24 mmol) of ethyl3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 59, after additional purification by means of preparativeHPLC (Method 8), 76 mg (63% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.08 min; m/z=502 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.30 (s, 6H), 2.47 (s, 3H), 3.14 (s,3H), 5.11 (s, 2H), 7.19-7.24 (m, 1H), 7.25-7.28 (m, 1H), 7.32-7.43 (m,2H), 7.51 (d, 1H), 7.61 (d, 1H), 8.48 (s, 1H), 12.74 (br.s, 1H).

Example 2063-[2-chloro-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121, with a reaction time of 2 h, except that MTBE wasreplaced by cyclohexane for the workup. Proceeding from 125 mg (0.35mmol) of ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 60, 134 mg (65% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.08 min; m/z=522 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.30 (s, 6H), 3.15 (s, 3H), 5.17 (s,2H), 7.19-7.24 (m, 1H), 7.24-7.27 (m, 1H), 7.48-7.56 (m, 2H), 7.58-7.62(m, 1H), 7.78-7.83 (m, 1H), 8.49 (s, 1H), 12.74 (br.s, 1H).

Example 2073-[3-chloro-2-(trifluoromethyl)benzyl]-2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121, with a reaction time of 45 min. Proceeding from 122 mg(0.22 mmol) of ethyl3-[3-chloro-2-(trifluoromethyl)benzyl]-2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 61, 87 mg (71% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.12 min; m/z=522 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.30 (s, 6H), 3.15 (s, 3H), 5.24(br.s, 2H), 7.19-7.23 (m, 1H), 7.23-7.26 (m, 1H), 7.33-7.37 (m, 1H),7.51 (d, 1H), 7.57-7.67 (m, 2H), 8.50 (s, 1H), 12.73 (br.s, 1H).

Example 208ethyl-3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-ethyl-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

371 mg (0.69 mmol) of ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 68 in THF (5 ml) were initially charged at 0° C. underargon, and 29 mg (content 60%, 0.72 mmol) of sodium hydride were added.The mixture was stirred at RT for 30 min and then cooled again to 0° C.A solution of 113 mg (0.72 mmol) of iodoethane in 1 ml of THF was addeddropwise. The reaction mixture was left to stir at RT for 2 days. Forworkup, the mixture was admixed with water and extracted twice withethyl acetate. The combined organic phases were dried over magnesiumsulphate and concentrated. The residue was purified by means ofpreparative HPLC (Method 7). This gave 50 mg (12% of theory) of thetitle compound.

LC-MS (Method 1): R_(t)=1.37 min; m/z=564 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.16 (t, 3H), 1.24 (t, 3H), 1.30 (s,6H), 3.70 (q, 2H), 4.20 (q, 2H), 5.16 (s, 2H), 7.21 (dd, 1H), 7.31 (d,1H), 7.49-7.60 (m, 3H), 7.78-7.82 (m, 1H), 8.52 (s, 1H).

Example 2091-(4-methylquinolin-7-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid hydrochloride

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 200 mg (0.40 mmol) of ethyl1-(4-methylquinolin-7-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 99, 173 mg (91% of theory) of the title compound wereobtained.

LC-MS (Method 3): R_(t)=1.25 min; m/z=470 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.48 (s, 3H), 2.80 (s, 3H), 3.80(br.s, 1H), 5.14 (s, 2H), 7.34-7.40 (m, 1H), 7.46-7.51 (m, 1H),7.59-7.65 (m, 2H), 7.84-7.90 (m, 1H), 8.28-8.36 (m, 2H), 8.68 (s, 1H),8.93-8.98 (m, 1H), 12.75 (br.s, 1H).

Example 2103-[2-chloro-3-(trifluoromethyl)benzyl]-1-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

228 mg (0.40 mmol) of the compound from Example 69 in 4.4 ml of glacialacetic acid/conc. hydrochloric acid 2:1 (v/v) were stirred at 120° C.(bath temperature) for 1 h. After cooling to RT, the mixture was admixedwith water and extracted three times with dichloromethane. The combinedorganic phases were dried over magnesium sulphate and concentrated on arotary evaporator. The residue was stirred in MTBE, and the solid formedwas filtered off, washed with a little MTBE and dried under HV. Thisgave 160 mg (80% of theory) of the title compound.

LC-MS (Method 5): R_(t)=1.23 min; m/z=494 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.25 (s, 6H), 3.25 (s, 2H), 5.15 (s,2H), 5.88 (br.s, 1H), 6.59 (s, 1H), 6.65 (d, 1H), 7.09 (d, 1H),7.47-7.55 (m, 1H), 7.56-7.61 (m, 1H), 7.80 (d, 1H), 8.36 (s, 1H), 12.67(br.s, 1H).

Example 2111-(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-3-[2-chloro-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

160 mg (0.32 mmol) of the compound from Example 210 were initiallycharged in THF (1.4 ml), then 90 μl (0.65 mmol) of triethylamine and 34μl (0.36 mmol) of acetic anhydride were added and the mixture wasstirred at RT overnight. Thereafter, the reaction mixture was admixedwith 1M hydrochloric acid and extracted three times withdichloromethane. The combined organic phases were dried over magnesiumsulphate, filtered and concentrated. The residue was stirred withmethanol, and the solid was filtered off and dried under reducedpressure. This gave 85 mg (47% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.13 min; m/z=536 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.34 (s, 6H), 2.18 (s, 3H), 3.94 (s,2H), 5.15 (s, 2H), 7.16-7.21 (m, 1H), 7.38-7.43 (m, 1H), 7.48-7.54 (m,1H), 7.61-7.65 (m, 1H), 7.77-7.82 (m, 1H), 8.13-8.16 (m, 1H), 8.42 (s,1H), 12.69 (br.s, 1H).

Example 2121-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

Analogously to Example 210, 253 mg (0.47 mmol) of the compound fromExample 70 were hydrolysed and the product was purified. This gave 174mg (77% of theory) of the title compound.

LC-MS (Method 5): R_(t)=1.23 min; m/z=474 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.24 (s, 6H), 2.46 (s, 3H), 3.24 (s,2H), 5.09 (s, 2H), 5.86 (br.s, 1H), 6.58 (s, 1H), 6.64 (d, 1H), 7.08 (d,1H), 7.26-7.45 (m, 2H), 7.60 (d, 1H), 8.35 (s, 1H), 12.68 (br.s, 1H).

Example 2131-(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were analogous toExample 211. Proceeding from 174 mg (0.36 mmol) of1-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid from Example 212, 135 mg (70% of theory) of the title compound wereobtained.

LC-MS (Method 5): R_(t)=1.18 min; m/z=516 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.34 (s, 6H), 2.18 (s, 3H), 2.46 (s,3H), 3.93 (s, 2H), 5.09 (s, 2H), 7.16-7.21 (m, 1H), 7.31-7.37 (m, 1H),7.38-7.44 (m, 1H), 7.57-7.62 (m, 1H), 8.12-8.15 (m, 1H), 8.40 (s, 1H),12.69 (br.s, 1H).

Example 2141-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were analogous toExample 121. Proceeding from 267 mg (0.51 mmol) of ethyl1-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-[2-methyl-3-(trifluoromethyl)-benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 102, 218 mg (83% of theory) of the title compound wereobtained.

LC-MS (Method 3): R_(t)=1.28 min; m/z=488 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.47 (s, 3H), 2.56-2.61 (m, 2H),2.89-2.94 (m, 2H), 3.28 (s, 3H), 5.10 (s, 2H), 7.20-7.24 (m, 1H),7.32-7.46 (m, 4H), 7.58-7.62 (m, 1H), 8.43 (s, 1H), 12.72 (br.s, 1H).

Example 2151-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2,4-dioxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (R enantiomer)

The preparation and purification of the title compound were analogous toExample 121, with reaction time 45 min. Proceeding from 83 mg (0.15mmol) of ethyl1-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2,4-dioxo-3-[4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 103, 39 mg (46% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.10 min; m/z=500 (M+H)⁺.

¹H NMR (400 MHz, CDCl₃): δ [ppm]=2.42-2.52 (m, 1H), 2.63-2.66 (m, 1H,partly concealed by DMSO signal), 2.69 (t, 2H), 2.95 (t, 2H), 3.12-3.20(m, 1H, 3.37 (s, 3H), 3.48-3.60 (m, 1H), 6.60-6.71 (m, 1H), 7.06 (d,1H), 7.14 (s, 1H), 7.21 (d, 1H), 7.28-7.34 (m, 2H), 7.50-7.56 (m, 1H),8.55 (s, 1H), 12.49 (s, 1H).

Example 216 ethyl3-(2-methyl-3-nitrobenzyl)-1-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

200 mg (0.58 mmol) of ethyl1-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 119A were initially charged in acetonitrile (7.5 ml). 108mg (0.58 mmol) of 2-methyl-3-nitrobenzyl chloride, 160 mg (1.16 mmol) ofpotassium carbonate and 48 mg (0.29 mmol) of potassium iodide were addedand the mixture was stirred at 60° C. for 41 h. The mixture cooled to RTwas separated completely by preparative HPLC (Method 8) and the isolatedproduct was dried under HV. This gave 218 mg (75% of theory) of thetitle compound.

LC-MS (Method 3): R_(t)=1.13 min; m/z=495 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 2.41 (s, 3H), 4.21 (q,2H), 3.30 (s, partly concealed by water signal, 3H), 4.71 (s, 2H), 5.06(s, 2H), 7.22-7.32 (m, 3H), 7.36 (t, 1H), 7.41 (d, 1H), 7.72 (d, 1H),8.38 (s, 1H).

Example 2171-(3-isopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (R enantiomer)

122 mg (0.22 mmol) of the compound from Example 114 were heated in 3.8ml of glacial acetic acid/conc. hydrochloric acid 2:1 (v/v) to 120° C.(bath temperature) for 1 h. After cooling to RT, 30 ml of water wereadded and the precipitated product was filtered off with suction. Thesolid was washed with water and dried under HV. This gave 107 mg (91% oftheory) of the title compound.

LC-MS (Method 3): R_(t)=2.43 min; m/z=529 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.42 (d, 3H), 1.43 (d, 3H), 2.34-2.46(m, 1H), 2.52-2.64 (m, 1H), 3.04-3.16 (m, 1H), 3.31 (s, 3H), 3.37-3.50(m, 1H), 4.54 (sept, 1H), 6.51-6.62 (m, 1H), 6.88-7.01 (m, 3H),7.21-7.31 (m, 2H), 7.46 (d, 1H), 8.49 (s, 1H), 12.29 (br. s, 1H).

Example 2183-[2-chloro-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 200 mg (0.36 mmol) of ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 52, 161 mg (83% of theory) of the title compound wereobtained.

LC-MS (Method 3): R_(t)=1.29 min; m/z=522 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.30 (s, 6H), 3.18 (s, 3H), 5.17 (s,2H), 7.15 (d, 1H), 7.43-7.48 (m, 1H), 7.50-7.56 (m, 2H), 7.57-7.62 (m,1H), 7.78-7.83 (m, 1H), 8.46 (s, 1H), 12.73 (br.s, 1H).

Example 219 3-[2-methyl-3(trifluoromethyl)benzyl]-2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 200 mg (0.38 mmol) of ethyl3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 53, 153 mg (80% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.07 min; m/z=502 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.29 (s, 6H), 2.47 (s, 3H), 3.17 (s,3H), 5.11 (s, 2H), 7.15 (d, 1H), 7.32-7.42 (m, 2H), 7.46 (dd, 1H), 7.54(d, 1H), 7.58-7.64 (m, 1H), 8.45 (s, 1H), 12.73 (br.s, 1H).

Example 2203-[3-chloro-2-(trifluoromethyl)benzyl]-2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 109 mg (0.20 mmol) of ethyl3-[3-chloro-2-(trifluoromethyl)benzyl]-2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 54, 83 mg (79% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.10 min; m/z=522 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.29 (s, 6H), 3.17 (s, 3H), 5.24(br.s, 2H), 7.15 (d, 1H), 7.32-7.37 (m, 1H), 7.42-7.47 (m, 1H),7.50-7.54 (m, 1H), 7.57-7.67 (m, 2H), 8.47 (s, 1H), 12.71 (br.s, 1H).

Example 2213-[3-fluoro-2-(trifluoromethyl)benzyl]-2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 230 mg (0.43 mmol) of ethyl3-[3-fluoro-2-(trifluoromethyl)benzyl]-2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 55, 193 mg (85% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.02 min; m/z=506 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.29 (s, 6H), 3.17 (s, 3H), 5.22 (s,2H), 7.15 (d, 1H), 7.18-7.24 (m, 1H), 7.38-7.43 (m, 1H), 7.43-7.47 (m,1H), 7.52-7.54 (m, 1H), 7.63-7.70 (m, 1H), 8.46 (s, 1H), 12.72 (br.s,1H).

Example 2223-(2,3-dichlorobenzyl)-2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121. Proceeding from 200 mg (0.39 mmol) of ethyl3-(2,3-dichlorobenzyl)-2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 56, 173 mg (90% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=1.05 min; m/z=488 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.29 (s, 6H), 3.17 (s, 3H), 5.13 (s,2H), 7.15 (d, 1H), 7.22-7.27 (m, 1H), 7.34 (t, 1H), 7.45 (dd, 1H), 7.54(d, 1H), 7.57-7.61 (m, 1H), 8.45 (s, 1H), 12.72 (br.s, 1H).

Example 2232,4-dioxo-3-[4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (racemate)

The preparation and purification of the title compound were analogous toExample 13 l. Proceeding from 507 mg (0.93 mmol) of ethyl2,4-dioxo-3-[4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 57, after purification by means of HPLC (Method 8), 131 mg(26% of theory) of the title compound were obtained.

LC-MS (Method 5): R_(t)=1.15 min; m/z=514 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.29 (br.s, 6H), 2.38-2.47 (m, 1H),2.46-2.48 (m, 1H, concealed by DMSO signal), 3.03-3.14 (m, 1H), 3.17 (s,3H), 3.20-3.27 (m, 1H, partly concealed by water signal), 6.34-6.60 (m,1H), 7.08-7.18 (m, 1H), 7.33-7.46 (m, 2H), 7.47-7.58 (m, 3H), 8.38 (s,1H), 12.69 (br. s, 1H).

Example 2242,4-dioxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (R enantiomer)

Analogously to Example 217, 147 mg (0.27 mmol) of the compound fromExample 58 were hydrolysed and the product was isolated. This gave 120mg (84% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.14 min; m/z=514 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.29 (br.s, 6H), 2.39-2.46 (m, 1H),2.46-2.60 (m, 1H, concealed by DMSO signal), 3.04-3.18 (m, 1H), 3.17 (s,3H), 3.22-3.36 (m, 1H partly concealed by water signal), 6.34-6.61 (br.m, 1H), 7.13 (d, 1H), 7.33-7.46 (m, 2H), 7.47-7.57 (m, 3H), 8.38 (s,1H), 12.69 (br. s, 1H).

α_(D) ²⁰ [chloroform, c=0.385]=+130.1°.

Example 2253-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1′-methyl-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-5′-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were analogous toExample 131. Proceeding from 147 mg (0.26 mmol) of ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-methyl-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-5′-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 65, after purification by means of HPLC (Method 7), 30 mg(21% of theory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.08 min; m/z=520 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.55-1.60 (m, 2H), 1.65-1.70 (m, 2H),3.26 (s, 3H), 5.16 (s, 2H), 7.20-7.23 (m, 2H), 7.41-7.46 (m, 1H),7.50-7.55 (m, 1H), 7.56-7.60 (m, 1H), 7.78-7.83 (m, 1H), 8.46 (s, 1H),12.73 (br.s, 1H).

Example 2261-(1′-methyl-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-5′-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were analogous toExample 131. Proceeding from 130 mg (0.24 mmol) of ethyl1-(1′-methyl-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-5′-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 66, after purification by means of HPLC (Method 7), 27 mg(22% of theory) of the title compound were obtained.

LC-MS (Method 1): R_(t)=1.08 min; m/z=500 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.55-1.60 (m, 2H), 1.65-1.69 (m, 2H),2.46 (s, 3H), 3.26 (s, 3H), 5.10 (s, 2H), 7.18-7.24 (m, 2H), 7.32-7.40(m, 2H), 7.42-7.46 (m, 1H), 7.59-7.63 (m, 1H), 8.45 (s, 1H), 12.73(br.s, 1H).

Example 2271-(1′-methyl-2′-oxo-1,2′-dihydrospiro[cyclopropane-1,3-indole]-5′-yl)-2,4-dioxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (R enantiomer)

7.81 g (92% purity, 13.31 mmol) of ethyl1-(1-methyl-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-5′-yl)-2,4-dioxo-3-[4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 67 in 117 ml of a mixture of acetic acid/water/conc.sulphuric acid (12:8:1) were stirred at 120° C. for 2.5 h. The cooledreaction mixture was admixed with water, and the precipitated solid wasfiltered off with suction, washed with water and dried under highvacuum. The mother liquor was extracted twice with dichloromethane. Thecombined organic phases were dried over sodium sulphate andconcentrated. The residue was purified by means of HPLC (Method 7)together with the previously isolated solid. The isolated product (95%purity) was dissolved in boiling 2-propanol and the solution was cooledovernight. The solid formed was filtered off with suction, washed with2-propanol and then dried under high vacuum. This gave 5.22 g (74% oftheory) of the title compound.

LC-MS (Method 1): R_(t)=1.08 min; m/z=512 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.46-1.53 (m, 2H), 1.62-1.69 (m, 2H),2.31-2.44 (m, 1H), 2.50-2.63 (m, 1H), 3.04-3.14 (m, 1H), 3.20 (s, 3H),3.35-3.48 (m, 1H), 6.50-6.60 (m, 1H), 6.71 (br.s, 1H), 6.90 (d, 1H),7.08-7.16 (m, 1H), 7.20-7.29 (m, 2H), 7.42-7.49 (m, 1H), 8.44 (s, 1H).

Example 2283-[(3-chloro-4-methyl-2-thienyl)methyl]-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

22 mg (43 μmol) of the compound from Example 105 in 1 ml of glacialacetic acid/conc. hydrochloric acid 2:1 were heated to 120° C. (bathtemperature) for 4 h. After cooling to RT, 10 ml of water were added andthe precipitated product was filtered off with suction. The solid wasstirred with diethyl ether, filtered off with suction again and driedunder HV. This gave 15 mg (74% of theory) of the title compound.

LC-MS (Method 1): R_(t)=0.97 min; m/z=461 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.12 (s, 3H), 3.33 (s, 3H), 3.37 (s,3H), 5.21 (s, 2H), 7.20 (dd, 1H), 7.27 (d, 1H), 7.30 (s, 1H), 7.37 (d,1H), 8.37 (s, 1H), 12.74 (br. s, 1H).

Example 2291-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (R enantiomer)

6.20 g (11.3 mmol) of the compound from Example 51 in 150 ml of glacialacetic acid/conc. hydrochloric acid 2:1 were heated to 120° C. (bathtemperature) for 1 h. After cooling to RT, the reaction mixture waspoured into 1 l of ice-water. The precipitated product was filtered offwith suction. The solid was stirred with diethyl ether, filtered offwith suction again and dried under HV. This gave 5.04 g (88% of theory)of the title compound.

LC-MS (Method 5): R_(t)=1.14 min; m/z=504 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=2.39-2.53 (m, 1H), 2.60-2.72 (m, 1H),3.12-3.24 (m, 1H), 3.42-3.56 (m, 4H), 6.58-6.71 (m, 1H), 7.15 (d, 1H),7.26-7.38 (m, 3H), 7.45 (s, 1H), 7.50-7.58 (m, 1H), 8.55 (s, 1H).

For further batches of the title compound, which have been preparedanalogously, the following additional data have been collected:

α_(D) ²⁰ [chloroform, c=0.365]=+148.6°.

Example 2301-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-(5-methoxy-2,3-dihydro-1H-inden-1-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (racemate)

86 mg (0.18 mmol) of the compound from Example 120 and 49 mg (0.58 mmol)of sodium hydrogencarbonate in 2 ml of acetonitrile and 2 ml of waterwere heated to reflux for 6 h. After cooling to RT, the mixture wasacidified by addition of 1N hydrochloric acid and separated directly bymeans of preparative HPLC (Method 7). This gave 24 mg (29% of theory) ofthe title compound.

LC-MS (Method 1): R_(t)=0.90 min; m/z=463 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.31-2.47 (m, 2H), 2.83-2.95 (m, 1H),3.09-3.22 (m, 1H), 3.34 (s, 6H), 3.72 (s, 3H), 6.29-6.47 (m, 1H),6.67-6.74 (m, 1H), 6.79 (s, 1H), 7.08 (d, 1H), 7.13-7.21 (m, 1H),7.22-7.30 (m, 1H), 7.37 (s, 1H), 8.38 (s, 1H), 12.74 (br. s, 1H).

Example 2313-(4,6-difluoro-2,3-dihydro-1H-inden-1-yl)-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (racemate)

Analogously to Example 217, 173 mg (0.35 mmol) of the compound fromExample 106 were hydrolysed. This gave 130 mg (80% of theory) of thetitle compound.

LC-MS (Method 5): R_(t)=0.99 min; m/z=469 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.38-2.48 (m, 2H, partly concealed byDMSO signal), 2.84-2.98 (m, 1H), 3.02-3.18 (m, 1H), 3.34 (br.s, 3H),6.22-6.60 (m, 1H), 7.03 (t, 2H), 7.12-7.29 (m, 2H), 7.31-7.43 (m, 1H),8.38 (s, 1H), 12.67 (br. s, 1H).

Example 232 1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5yl)-3-(6-methyl-2,3-dihydro-1H-inden-1-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (racemate)

127 mg (0.27 mmol) of the compound from Example 107 were initiallycharged in 2.5 ml of acetonitrile. 74 mg (0.88 mmol) of sodiumhydrogencarbonate and 2.5 ml of water were added and the mixture washeated to reflux for 6 h. After cooling to RT, the mixture was acidifiedwith 1N hydrochloric acid and separated completely by preparative HPLC(Method 7). This gave 78 mg (65% of theory) of the title compound.

LC-MS (Method 1): R_(t)=0.98 min; m/z=447 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.25 (s, 3H), 2.35-2.45 (m, 2H),2.82-2.93 (m, 1H), 3.04-3.18 (m, 1H), 3.31 (s, 3H), 3.36 (s, 3H),6.23-6.54 (m, 1H), 6.96-7.03 (m, 2H), 7.10 (d, 1H), 7.16-7.30 (m, 2H),7.33-7.45 (m, 1H), 8.39 (s, 1H), 12.73 (br. s, 1H).

Example 233 ethyl3-(4-methoxy-2,3-dihydro-1H-inden-1-yl)-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate)

Under argon, a solution of 200 mg (0.58 mmol) of the compound fromExample 31A and 453 mg (1.73 mmol) of triphenylphosphine in 15.8 ml ofTHF/DMF 1:1 (v/v) was admixed dropwise with 227 μl (1.15 mmol) ofdiisopropyl azodicarboxylate. Then 123 mg (0.75 mmol) of the compoundfrom Example 103A were added and the mixture was stirred at RT for 1 h.While cooling with ice, 2 ml of 1N hydrochloric acid were added, and themixture was stirred further for 15 min and then separated by preparativeHPLC (Method 7). This gave 118 mg (41% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.05 min; m/z=494 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 2.26-2.46 (m, 2H),2.73-2.85 (m, 1H), 2.95-3.10 (m, 1H), 3.44 (s, 3H), 3.77 (s, 3H),4.09-4.27 (m, 2H), 6.25-6.57 (m, 1H), 6.74 (d, 1H), 6.78 (d, 1H), 7.12(t, 1H), 7.35-7.64 (m, 2H), 7.83 (br.s, 1H), 8.38 (s, 1H).

Example 2343-(4-methoxy-2,3-dihydro-1H-inden-1-yl)-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (racemate)

115 mg (0.23 mmol) of the compound from Example 233 in 7.2 ml of glacialacetic acid/conc. hydrochloric acid 2:1 (v/v) was heated to reflux for 1h. After cooling to RT, the whole reaction mixture was separated bypreparative HPLC (Method 7). This gave 42 mg (39% of theory) of thetitle compound.

LC-MS (Method 1): R_(t)=1.03 min; m/z=466 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=2.26-2.38 (m, 1H), 2.44-2.56 (m, 1H),2.78-2.89 (m, 1H), 3.07-3.19 (m, 1H), 3.38 (s, 3H), 3.75 (s, 3H),6.46-6.58 (m, 1H), 6.62-6.73 (m, 2H), 7.02-7.14 (m, 2H), 7.18-7.28 (m,1H), 7.37 (br.s, 1H), 8.44 (s, 1H).

Example 2353-(4,6-difluoro-2,3-dihydro-1H-inden-1-yl)-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (racemate)

170 mg (0.34 mmol) of the compound from Example 108 in 7 ml of glacialacetic acid and 3.5 ml of conc. hydrochloric acid was heated to refluxfor 1 h. After cooling to RT, the reaction mixture was purified bypreparative HPLC (Method 7). This gave 133 mg (83% of theory) of thetitle compound.

LC-MS (Method 1): R_(t)=1.07 min; m/z=472 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=2.32-2.45 (m, 1H), 2.52-2.64 (m, 1H),2.84-2.97 (m, 1H), 3.14-3.26 (m, 1H), 3.38 (s, 3H), 6.44-6.56 (m, 1H),6.58-6.70 (m, 2H), 7.07 (d, 1H), 7.23 (d, 2H), 7.37 (br.s, 1H), 8.46 (s,1H).

Example 2363-(6-methyl-2,3-dihydro-1H-inden-1-yl)-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (racemate)

127 mg (0.27 mmol) of the compound from Example 109 were hydrolysedunder alkaline conditions analogously to Example 232 and the product waspurified. This gave 56 mg (47% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.10 min; m/z=450 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=2.22 (s, 3H), 2.28-2.39 (m, 1H),2.43-2.55 (m, 1H), 2.82-2.94 (m, 1H), 3.12-3.24 (m, 1H), 3.38 (s, 3H),6.44-6.55 (m, 1H), 6.86 (s, 1H), 6.98 (d, 1H), 7.02-7.12 (m, 2H), 7.24(d, 1H), 7.38 (br.s, 1H), 8.45 (s, 1H).

Example 237 ethyl3-[6-chloro-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate)

Analogously to Example 233, 200 mg (0.58 mmol) of the compound fromExample 2A were reacted with 179 mg (0.76 mmol) of6-chloro-4-(trifluoromethyl)indan-1-ol from Example 108A and the productwas isolated. This gave 260 mg (69% of theory) of the title compound in87% purity.

LC-MS (Method 1): R_(t)=1.14 min; m/z=563 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (br. t, 3H), 2.36-2.55 (m, 2H,partly concealed by DMSO signal), 3.00-3.14 (m, 1H), 3.14-3.29 (m, 1H),3.31 (s, 3H), 3.37 (s, 3H), 4.13-4.25 (m, 2H), 6.29-6.54 (m, 1H),7.18-7.31 (m, 2H), 7.39 (br.s, 1H), 7.59 (s, 1H), 7.68 (br.s, 1H), 8.34(s, 1H).

Example 2383-[6-chloro-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (racemate)

Analogously to Example 217, 260 mg (0.46 mmol) of the compound fromExample 237 were hydrolysed and the product was isolated. This gave 200mg (79% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.09 min; m/z=535 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=2.35-2.46 (m, 1H), 2.58 (s, 1H),3.00-3.12 (m, 1H), 3.31 (s, 3H), 3.33 (s, 3H), 3.35-3.44 (m, 1H),6.49-6.60 (m, 1H), 6.87 (s, 1H), 6.96 (s, 2H), 7.27 (s, 1H), 7.45 (s,1H), 8.50 (s, 1H).

Example 239 ethyl3-[6-bromo-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate)

Analogously to Example 233, 226 mg (0.66 mmol) of the compound fromExample 2A were reacted with 240 mg (0.85 mmol) of6-bromo-4-(trifluoromethyl)indan-1-ol from Example 113A and the productwas isolated. This gave 230 mg (58% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.17 min; m/z=607/609 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.23 (t, 2H), 2.28-2.43 (m, 1H), 2.52(dtd, 1H), 3.00 (dt, 1H), 3.31 (s, 3H), 3.33 (s, 2H), 3.29-3.41 (m, 1H,partly concealed by the methyl signals), 4.21 (q, 2H), 6.42-6.65 (m,1H), 6.88 (br.s, 1H), 6.96 (s, 2H), 7.40 (s, 1H), 7.54 (s, 1H), 8.24 (s,1H).

Example 2403-[6-bromo-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (racemate)

Analogously to Example 217, 52 mg (86 mol) of the compound from Example238 were hydrolysed and the product was isolated. This gave 23 mg (46%of theory) of the title compound.

LC-MS (Method 5): R_(t)=1.15 min; m/z=579 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=2.41-2.54 (m, 1H), 2.61-2.74 (m, 1H),3.06-3.18 (m, 1H), 3.39 (s, 3H), 3.42 (s, 3H), 3.43-3.51 (m, 1H),6.57-6.69 (m, 1H), 6.95 (s, 1H), 7.05 (s, 2H), 7.50 (s, 1H), 7.67 (s,1H), 8.58 (s, 1H),

Example 2411-[1-methyl-2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzimidazol-5-yl]-2,4-dioxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (R enantiomer)

Analogously to Example 217, 370 mg (0.62 mmol) of the compound fromExample 28 were hydrolysed and the product was isolated. This gave 314mg (89% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.15 min; m/z=569 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=2.32-2.46 (m, 1H), 2.51-2.65 (m, 1H),3.03-3.17 (m, 1H), 3.36 (s, 3H), 3.40-3.48 (m, 1H), 4.41 (q, 2H),6.51-6.63 (m, 1H), 6.96 (s, 1H), 7.00-7.09 (m, 2H), 7.21-7.30 (m, 2H),7.46 (d, 1H), 8.48 (s, 1H).

Example 2421-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[6-fluoro-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (racemate)

Analogously to Example 217, 63 mg (115 mol) of the compound from Example110 were hydrolysed and the product was isolated. This gave 47 mg (78%of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.09 min; m/z=519 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=2.44-2.57 (m, 1H), 2.63-2.76 (m, 1H),3.07-3.19 (m, 1H), 3.39 (s, 3H), 3.42 (s, 3H), 3.43-3.50 (m, 1H),6.56-6.68 (m, 1H), 6.94 (s, 1H), 7.01-7.10 (m, 3H), 7.23-7.30 (m, 1H),8.58 (s, 1H), 12.36 (br. s, 1H).

Example 2431-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (R enantiomer)

Analogously to Example 217, 600 mg (1.17 mmol) of the compound fromExample 112 were hydrolysed (reaction time 4 h) and the product wasisolated. This gave 540 mg (89% of theory) of the title compound.

LC-MS (Method 3): R_(t)=2.20 min; m/z=487 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=2.32-2.45 (m, 1H), 2.51-2.64 (m, 1H),3.02-3.17 (m, 1H), 3.31 (s, 3H), 3.36-3.47 (m, 1H), 6.52-6.61 (m, 1H),6.96 (s, 3H), 7.21-7.31 (m, 2H), 7.42-7.50 (m, 1H), 8.14 (s, 1H), 8.47(s, 1H), 12.36 (br. s, 1H).

Example 2441-(3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (R enantiomer)

Analogously to Example 217, 73 mg (0.14 mmol) of the compound fromExample 113 were hydrolysed and the product was isolated. This gave 58mg (82% of theory) of the title compound.

LC-MS (Method 3): R_(t)=2.36 min; m/z=515 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.22 (t, 3H), 2.33-2.45 (m, 1H),2.52-2.64 (m, 1H), 3.04-3.17 (m, 1H), 3.33 (s, 3H), 3.37-3.48 (m, 1H),3.83 (q, 2H), 6.51-6.61 (m, 1H), 6.87 (s, 1H), 6.92-7.01 (m, 2H),7.21-7.31 (m, 2H), 7.46 (d, 1H), 8.49 (s, 1H), 12.35 (br. s, 1H).

Example 2451-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-3-[7-(trifluoromethyl)-2,3-dihydro-1-benzofur-3-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (racemate)

Analogously to Example 234, 32 mg (60 mol) of the compound from Example119 were hydrolysed and the product was isolated. This gave 19 mg (63%of theory) of the title compound.

LC-MS (Method 5): R_(t)=1.04 min; m/z=506 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=3.38 (s, 3H), 4.74-4.88 (m, 2H), 6.79(dd, 1H), 6.91 (t, 1H), 7.07 (d, 1H), 7.21 (dd, 1H), 7.33 (d, 1H), 7.37(d, 1H), 7.41 (d, 1H), 8.47 (s, 1H), 11.67-12.36 (br.s., 1H).

Example 2461-[1-methyl-2-oxo-3-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydro-1H-benzimidazol-5-yl]-2,4-dioxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (diastereomer mixture)

Analogously to Example 217, 180 mg (0.29 mmol) of the compound fromExample 115 were hydrolysed and the product was isolated. This gave 152mg (83% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.11 min; m/z=599 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=2.32-2.46 (m, 1H), 2.52-2.65 (m, 1H),3.03-3.16 (m, 1H), 3.37 (s, 3H), 3.42-3.51 (m, 1H), 3.99-4.08 (m, 1H),4.16 (d, 1H), 4.22-4.37 (m, 2H), 6.50-6.64 (m, 1H), 7.03 (d, 3H),7.20-7.32 (m, 2H), 7.46 (d, 1H), 8.47 (s, 1H), 12.29 (br. s, 1H).

Example 2471-[1-methyl-2-oxo-3-(3,3,3-trifluoropropyl)-2,3-dihydro-1H-benzimidazol-5-yl]-2,4-dioxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (R enantiomer)

Analogously to Example 217, 160 mg (0.26 mmol) of the compound fromExample 116 were hydrolysed and the product was isolated. This gave 140mg (91% of theory) of the title compound.

LC-MS (Method 5): R_(t)=1.16 min; m/z=583 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=2.47-2.58 (m, 1H), 2.60-2.77 (m, 3H),3.17-3.29 (m, 1H), 3.47 (s, 3H), 3.49-3.61 (m, 1H), 4.16 (t, 2H),6.63-6.76 (m, 1H), 7.00 (s, 1H), 7.08-7.16 (m, 2H), 7.35-7.44 (m, 2H),7.59 (d, 1H), 8.61 (s, 1H), 12.46 (br. s, 1H).

Example 2481-(3-cyclopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (R enantiomer)

Analogously to Example 234, 160 mg (0.26 mmol) of the compound fromExample 117 were hydrolysed. The reaction mixture was diluted with 5 mlof acetonitrile and purified by preparative HPLC (Method 7). This gave140 mg (91% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.07 min; m/z=527 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=0.84-0.93 (m, 2H), 0.95-1.03 (m, 2H),2.34-2.48 (m, 1H), 2.52-2.64 (m, 1H), 2.73-2.83 (m, 1H), 3.05-3.16 (m,1H), 3.28 (s, 3H), 3.36-3.49 (m, 1H), 6.51-6.63 (m, 1H), 6.89-6.99 (m,2H), 7.06 (s, 1H), 7.21-7.32 (m, 2H), 7.46 (d, 1H), 8.49 (s, 1H).

Example 249 ethyl3-(4,6-dichloro-2,3-dihydro-1H-inden-1-yl)-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate)

Under argon, 101 mg (0.29 mmol) of the compound from Example 31A, 71 mg(0.35 mmol) of 4,6-dichloroindan-1-ol from Example 114A and 137 mg (0.52mmol) of triphenylphosphine were initially charged in 8 ml of THF/DMF1:1 (v/v), and 97 μl (0.49 mmol) of diisopropyl azodicarboxylate wereadded dropwise. The mixture was stirred at RT for 1 h. While coolingwith ice, 2 ml of 1N hydrochloric acid were added, and the mixture wasstirred further for 15 min and then purified completely by means ofpreparative HPLC (Method 7). This gave 101 mg (65% of theory) of thetitle compound.

LC-MS (Method 1): R_(t)=1.20 min; m/z=532 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.36 (t, 3H), 2.37-2.52 (m, 1H), 2.63(dtd, 1H), 2.93-3.08 (m, 1H), 3.25-3.40 (m, 1H), 3.51 (s, 3H), 4.34 (q,2H), 6.65 (br.s, 1H), 7.09 (s, 1H), 7.19 (d, 1H), 7.29 (s, 1H), 7.36 (d,1H), 7.50 (br.s, 1H), 8.34 (s, 1H).

Example 2503-(4,6-dichloro-2,3-dihydro-1H-inden-1-yl)-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (racemate)

Analogously to Example 217, 106 mg (0.20 mmol) of the compound fromExample 249 were hydrolysed and the product was isolated. This gave 74mg (73% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.17 min; m/z=505 (M+H)⁺.

¹H NMR (500 MHz, CD₂Cl₂): δ [ppm]=2.37-2.51 (m, 1H), 2.60-2.70 (m, 1H),2.95-3.06 (m, 1H), 3.24-3.36 (m, 1H), 3.47 (s, 3H), 6.54-6.71 (m, 1H),7.07 (s, 1H), 7.12-7.20 (m, 1H), 7.29 (s, 1H), 7.31-7.38 (m, 1H),7.41-7.54 (m, 1H), 8.56 (s, 1H).

Example 251 ethyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-{1-[2-methyl-3-(trifluoromethyl)phenyl]-ethyl}-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate)

Under argon, 250 mg (0.73 mmol) of the compound from Example 2A, 198 mg(90% purity, 0.87 mmol) of 1-[2-methyl-3-(trifluoromethyl)phenyl]ethanolfrom Example 15A and 324 mg (1.23 mmol) of triphenylphosphine wereinitially charged in 6.5 ml of THF/DMF 1:2 (v/v), and 229 μl (1.16 mmol)of diisopropyl azodicarboxylate were added dropwise. The mixture wasstirred at RT for 1 h. While cooling with ice, 1 ml of 1N hydrochloricacid was added, and the mixture was stirred further for 10 min and thenpurified by preparative HPLC (Method 7). This gave 153 mg (40% oftheory) of the title compound.

LC-MS (Method 1): R_(t)=1.05 min; m/z=531 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.30 (t, 3H), 1.87 (d, 3H), 2.34 (s,3H), 3.38 (s, 3H), 3.40 (s, 3H), 4.27 (q, 2H), 6.30 (q, 1H), 6.90 (d,1H), 6.95-7.07 (m, 2H), 7.31 (t, 1H), 7.58 (d, 1H), 7.92 (d, 1H), 8.28(s, 1H).

Example 2521-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-{1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (racemate)

Analogously to Example 217, 140 mg (0.26 mmol) of the compound fromExample 251 were hydrolysed and the product was isolated. This gave 79mg (58% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.08 min; m/z=503 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.92 (d, 3H), 2.35 (s, 3H), 3.38 (s,3H), 3.41 (s, 3H), 6.35 (q, 1H), 6.90 (d, 1H), 6.97-7.05 (m, 2H), 7.34(t, 1H), 7.62 (d, 1H), 7.93 (d, 1H), 8.53 (s, 1H), 12.5 (br.s, 1H).

By preparative HPLC on a chiral phase (Method 16), the product wasseparated into its enantiomers: see Examples 253 and 254.

Example 2531-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-{1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (enantiomer 1)

Enantiomer eluting first from the preparative separation of 65 mg of thecompound from Example 252 by Method 16. After drying under HV, 25 mg ofthe title compound were obtained.

Chiral analytical HPLC (Method 17): R_(t)=10.6 min

Example 2541-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-{1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (enantiomer 2)

Enantiomer eluting last from the preparative separation of 65 mg of thecompound from Example 252 by Method 16. After drying under HV, 28 mg ofthe title compound were obtained.

Chiral analytical HPLC (Method 17): R_(t)=11.5 min

Example 255 ethyl3-{1-[2-chloro-3-(trifluoromethyl)phenyl]ethyl}-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate)

Analogously to Example 251, 500 mg (1.51 mmol) of the compound fromExample 28A were reacted with 508 mg (80% purity, 1.81 mmol) of1-[2-chloro-3-(trifluoromethyl)phenyl]ethanol from Example 116A and theproduct was purified. This gave 435 mg (54% of theory) of the titlecompound.

LC-MS (Method 4): R_(t)=2.38 min; m/z=538 (M+H)⁺.

¹H NMR (500 MHz, CD₂Cl₂): δ [ppm]=1.22-1.35 (m, 3H), 1.87 (d, 3H), 3.40(s, 3H), 4.26 (q, 2H), 6.30 (q, 1H), 7.05 (d, 1H), 7.11-7.17 (m, 1H),7.20 (d, 1H), 7.42 (t, 1H), 7.67 (d, 1H), 7.97 (d, 1H), 8.23 (s, 1H).

Example 2563-{1-[2-chloro-3-(trifluoromethyl)phenyl]ethyl}-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (racemate)

Analogously to Example 217, 400 mg (0.74 mmol) of the compound fromExample 255 were hydrolysed and the product was isolated. This gave 320mg (84% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.04 min; m/z=510 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.91 (d, 3H), 3.41 (s, 3H), 6.37 (q,1H), 7.05-7.09 (m, 1H), 7.15 (dd, 1H), 7.21 (d, 1H), 7.45 (t, 1H), 7.71(d, 1H), 7.97 (d, 1H), 8.50 (s, 1H), 12.37 (br. s, 1H).

By preparative HPLC on a chiral phase (Method 18), the product wasseparated into its enantiomers: see Examples 257 and 258.

Example 2573-{1-[2-chloro-3-(trifluoromethyl)phenyl]ethyl}-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (enantiomer 1)

Enantiomer eluting first from the preparative separation of 300 mg ofthe compound from Example 256 by Method 18. After drying under HV, 129mg of the title compound were obtained.

Chiral analytical HPLC (Method 19): R_(t)=74 min

Example 2583-{1-[2-chloro-3-(trifluoromethyl)phenyl]ethyl}-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (enantiomer 2)

Enantiomer eluting last from the preparative separation of 300 mg of thecompound from Example 256 by Method 18. After drying under HV, 128 mg ofthe title compound were obtained.

Chiral analytical HPLC (Method 19): 16.6 min

Example 259 ethyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-3-{1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate)

Analogously to Example 251, 500 mg (1.51 mmol) of the compound fromExample 28A were reacted with 411 mg (90% purity, 1.81 mmol) of1-[2-methyl-3-(trifluoromethyl)phenyl]ethanol from Example 115A and theproduct was purified. This gave 285 mg (36% of theory) of the titlecompound.

LC-MS (Method 1): R_(t)=1.09 min; m/z=518 (M+H)⁺.

¹H NMR (500 MHz, CD₂Cl₂): δ [ppm]=1.30 (t, 3H), 1.86 (d, 3H), 2.33 (s,3H), 3.40 (s, 3H), 4.27 (q, 2H), 6.29 (q, 1H), 7.04 (d, 1H), 7.10-7.15(m, 1H), 7.18 (d, 1H), 7.31 (t, 1H), 7.58 (d, 1H), 7.91 (d, 1H), 8.24(s, 1H).

Example 2601-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-3-{1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (racemate)

Analogously to Example 217, 260 mg (0.50 mmol) of the compound fromExample 259 were hydrolysed and the product was isolated. This gave 200mg (81% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.07 min; m/z=490 (M+H)⁺.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.91 (d, 3H), 2.34 (s, 3H), 3.41 (s,3H), 6.35 (q, 1H), 7.07 (d, 1H), 7.14 (dd, 1H), 7.20 (d, 1H), 7.34 (t,1H), 7.62 (d, 1H), 7.92 (d, 1H), 8.51 (s, 1H), 12.43 (br. s, 1H).

By preparative HPLC on a chiral phase (Method 20), it was possible toseparate the product into its enantiomers: see Examples 261 and 262.

Example 2611-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-3-{1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (enantiomer 1)

Enantiomer eluting first from the preparative separation of 190 mg ofthe compound from Example 256 by Method 20. After drying under HV, 80 mgof the title compound were obtained.

Chiral analytical HPLC (Method 21): R_(t)=6.61 min

Example 2621-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-3-{1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (enantiomer 2)

Enantiomer eluting last from the preparative separation of 190 mg of thecompound from Example 256 by Method 20. After drying under HV, 82 mg ofthe title compound were obtained.

Chiral analytical HPLC (Method 21): R_(t)=10.6 min

Example 2631-(6-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121, proceeding from 130 mg (0.26 mmol) of ethyl1-(6-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 184. The crude product obtained was purified by means ofpreparative HPLC (Method 8). The concentrated product fractions werestirred with dichloromethane, and the solid was filtered off and driedunder reduced pressure. Thus, 67 mg (51% of theory) of the titlecompound were obtained.

LC-MS (Method 1): R_(t)=0.95 min; m/z=475 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.09 (s, 3H), 2.46 (s, 3H), 5.04-5.17(m, 2H), 6.88 (s, 1H), 7.10 (s, 1H), 7.36 (s, 2H), 7.58-7.62 (m, 1H),8.37 (s, 1H), 10.77-10.83 (m, 2H), 12.72 (br.s, 1H).

Example 2643-[2-chloro-3-(trifluoromethyl)benzyl]-1-(6-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121, with a reaction time of 1.5 h. Proceeding from 150 mg(0.29 mmol) of ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(6-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 185, 126 mg (84% of theory) of the title compound wereobtained.

LC-MS (Method 1): R_(t)=0.96 min; m/z=495 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.10 (s, 3H), 5.17 (s, 2H), 6.88 (s,1H), 7.10 (s, 1H), 7.50-7.60 (m, 2H), 7.78-7.83 (m, 1H), 8.39 (s, 1H),10.80 (s, 2H), 12.69 (br.s, 1H).

Example 2653-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-ethyl-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The preparation and purification of the title compound were in analogyto Example 121, with a reaction time of 30 min. Proceeding from 50 mg(0.09 mmol) of ethyl3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(1-ethyl-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 208, 26 mg (54% of theory) of the title compound wereobtained.

LC-MS (Method 3): R_(t)=1.37 min; m/z=536 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.11-1.19 (m, 3H), 1.30 (s, 6H),3.65-3.75 (m, 2H), 5.18 (s, 2H), 7.17-7.23 (m, 1H), 7.31 (s, 1H),7.48-7.57 (m, 2H), 7.57-7.63 (m, 1H), 7.77-7.85 (m, 1H), 8.52 (s, 1H),12.73 (br.s, 1H).

Example 266 ethyl1-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The preparation and purification were analogous to Example 216,proceeding from 200 mg (0.58 mmol) of ethyl1-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 119A and 147 mg (0.58 mmol) of2-methyl-3-(trifluoromethyl)benzyl bromide. This gave 168 mg (53% oftheory) of the title compound.

LC-MS (Method 3): R_(t)=1.26 min; m/z=518 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22 (t, 3H), 2.46 (s, 3H), 3.30 (s,partly concealed by water signal, 3H), 4.20 (q, 2H), 4.71 (s, 2H), 5.06(s, 2H), 7.22-7.32 (m, 3H), 7.32-7.41 (m, 2H), 7.59 (d, 1H), 8.39 (s,1H).

Example 2673-(2-methyl-3-nitrobenzyl)-1-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

185 mg (0.58 mmol) of the compound from Example 216 were dissolved in 5ml of glacial acetic acid and 2.5 ml of concentrated hydrochloric acidand stirred at 60° C. for 6 h. After cooling to RT, 75 ml of water wereadded. The precipitated solid was filtered off, washed with water anddried under HV. This gave 129 mg (70% of theory) of the title compound.

LC-MS (Method 1): R_(t)=0.96 min; m/z=467 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.41 (s, 3H), 3.30 (s, partlyconcealed by water signal, 3H), 4.72 (s, 2H), 5.10 (s, 2H), 7.22-7.32(m, 3H), 7.37 (t, 1H), 7.44 (d, 1H), 7.72 (d, 1H), 8.41 (s, 1H), 12.71(br. s, 1H).

Example 268 1-(4-methyl-3oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-3-[2-methyl-3(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

130 mg (0.25 mmol) of the compound from Example 267 were dissolved in 5ml of glacial acetic acid and 2.5 ml of concentrated hydrochloric acidand stirred at 60° C. for 6 h. After cooling to RT, 75 ml of water wereadded. The precipitated solid was filtered off, washed with water anddried under HV. This gave 109 mg (89% of theory) of the title compound.

LC-MS (Method 1): R_(t)=1.09 min; m/z=490 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=2.48 (s, 3H), 3.30 (s, partlyconcealed by water signal, 3H), 4.72 (s, 2H), 5.10 (s, 2H), 7.22-7.42(m, 5H), 7.60 (d, 1H), 8.42 (s, 1H), 12.70 (br. s, 1H).

Example 269 ethyl3-(5-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate)

400 mg (1.16 mmol) of ethyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(Example 2A), 255 mg (1.39 mmol) of5-chloro-1,2,3,4-tetrahydronaphthalen-1-ol and 518 mg (1.98 mmol) oftriphenylphosphine were dissolved in 5 ml of THF and 10 ml of DMF. 376mg (1.86 mmol) of DIAD were added and the mixture was stirred at RT for2 h. The reaction mixture was admixed with a little 1 M aqueoushydrochloric acid and separated completely by means of preparative HPLC(Method 15). This gave 510 mg (86% of theory) of the title compound.

LC/MS (Method 1): R_(t)=1.09; m/z=509 (M+H)⁺

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.23 (t, 3H), 1.61-1.80 (m, 1H),1.92-2.12 (m, 2H), 2.24-2.44 (m, 1H), 2.53-2.72 (m, 1H), 2.94 (br. d,1H), 3.30 (s, 3H), 3.32 (s, 3H), 4.21 (br. q, 2H), 6.16 (br. s., 1H),6.85 (d, 2H), 6.89-7.02 (m, 3H), 7.13 (d, 1H), 8.25 (s, 1H).

Example 2703-(5-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (racemate)

490 mg (0.96 mmol) of ethyl3-(5-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 269 were stirred in 3 ml of conc. hydrochloric acid and 7ml of glacial acetic acid at reflux temperature. On completion ofconversion, the reaction mixture was cooled and separated directly bymeans of preparative HPLC (Method 15).

This gave 369 mg (80% of theory) of the title compound.

LC/MS (Method 1): R_(t)=1.10 min; m/z=481 (M+H)⁺

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.74-1.91 (m, 1H), 2.07-2.24 (m, 2H),2.44 (q, 1H), 2.63-2.84 (m, 1H), 3.05 (d, 1H), 3.39 (s, 3H), 3.41 (s,3H), 6.27 (br. s., 1H), 6.84-6.98 (m, 2H), 6.98-7.15 (m, 3H), 7.25 (d,1H), 8.59 (s, 1H), 12.5 (br. s, 1H).

Example 271 methyl3-(5-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate)

To a solution of 300 mg (0.62 mmol) of3-(5-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid from Example 270 in 5 ml of methanol were added 680 μl (9.36 mmol)of thionyl chloride. The mixture was stirred at reflux temperature for 7hours, then concentrated on a rotary evaporator. The residue was driedunder high vacuum. This gave 302 mg (94% of theory) of the titlecompound.

LC/MS (Method 28): R_(t)=3.10 min; m/z=495 (M+H)⁺

Example 272 methyl3-(5-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(enantiomer 1)

Enantiomer which elutes first (56 mg) from the separation of 300 mg ofthe racemic substance from Example 271 by means of preparative HPLC on achiral phase (Method 29).

Chiral analytical HPLC (Method 30): R_(t)=6.14 min, >99% ee.

In order to remove solvent impurities, the resulting product waspurified by means of preparative HPLC (Method 15). This gave 49 mg ofthe title compound.

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.72-1.87 (m, 1H), 2.01-2.20 (m, 2H),2.33-2.50 (m, 1H), 2.62-2.79 (m, 1H), 3.03 (d, 1H), 3.38 (s, 3H), 3.41(s, 3H), 3.82 (br. s., 3H), 6.23 (br. s., 1H), 6.85-7.13 (m, 5H), 7.21(d, 1H), 8.36 (s, 1H).

Example 273 methyl3-(5-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(enantiomer 2)

Enantiomer which elutes last (92 mg) from the separation of 300 mg ofthe racemic substance from Example 271 by means of preparative HPLC on achiral phase (Method 29).

Chiral analytical HPLC (Method 30): R_(t)=7.29 min, 97% ee.

In order to remove solvent impurities, the resulting product waspurified by means of preparative HPLC (Method 15). This gave 68 mg ofthe title compound.

¹H NMR (400 MHz, CD₂Cl₂): δ [ππμ]=1.73-1.88 (μ, 1H), 2.01-2.21 (μ, 2H),2.33-2.51 (μ, 1H), 2.62-2.80 (μ, 1H), 3.03 (δ, 1H), 3.38 (σ, 3H), 3.41(σ, 3H), 3.82 (βρ. σ., 3H), 6.24 (βp. σ., 1H), 6.84-7.11 (μ, 5H), 7.21(δ, 1H), 8.36 (σ, 1H).

Example 2743-(5-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (enantiomer 1)

47 mg (0.10 mmol) of methyl3-(5-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(enantiomer 1) from Example 272 were stirred in 2 ml of glacial aceticacid/conc. hydrochloric acid (2:1 v/v) at reflux temperature for 2 h.The reaction mixture was concentrated on a rotary evaporator and theresidue was dissolved in acetonitrile/water and lyophilized. This gave38 mg (76% of theory) of the title compound.

LC/MS (Method 1): R_(t)=1.08 min; m/z=481 (M+H)⁺

Example 2753-(5-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (enantiomer 2)

66 mg (0.13 mmol) of methyl3-(5-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(enantiomer 2) from Example 273 were stirred in 2 ml of glacial aceticacid/conc. hydrochloric acid (2:1 v/v) at reflux temperature for 2 h.The reaction mixture was concentrated on a rotary evaporator and theresidue was dissolved in acetonitrile/water and lyophilized. This gave62 mg (87% of theory) of the title compound.

LC/MS (Method 1): R_(t)=1.08 min; m/z=481 (M+H)⁺

Example 276 ethyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate)

225 mg (0.66 mmol) of ethyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(Example 2A), 170 mg (0.79 mmol) of5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ol and 292 mg (1.11mmol) of triphenylphosphine in 3 ml of THF and 6 ml of DMF at RT wereadmixed with 212 mg (1.05 mmol) of DIAD. The mixture was stirred at RTfor 2 h, then admixed with a little 1M aqueous hydrochloric acid,diluted with DMSO and purified by means of preparative HPLC (Method 15).This gave 136 mg (38% of theory) of the title compound.

LC/MS (Method 1): R_(t)=1.14 min; m/z=543 (M+H)⁺

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.23 (t, 3H), 1.65-1.80 (m, 1H),1.99-2.11 (m, 2H), 2.25-2.41 (m, 1H), 2.74-2.92 (m, 1H), 2.99 (d, 1H),3.30 (s, 3H), 3.32 (s, 3H), 4.21 (q, 2H), 6.20 (br. s., 1H), 6.78-7.00(m, 3H), 7.09-7.18 (m, 2H), 7.40 (t, 1H), 8.25 (s, 1H).

Example 2771-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (racemate)

120 mg (0.22 mmol) of ethyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 276 were stirred with 2 ml of conc. aqueous hydrochloricacid and 4 ml of glacial acetic acid at reflux temperature for 2 h. Thereaction mixture was diluted with 5 ml of acetonitrile and purified bymeans of preparative HPLC (Method 15). This gave 54 mg (47% of theory)of the title compound.

LC/MS (Method 1): R_(t)=1.12 min; m/z=515 (M+H)⁺

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.74-1.91 (m, 1H), 2.12-2.24 (m, 2H),2.35-2.50 (m, 1H), 2.85-2.99 (m, 1H), 3.04-3.15 (m, 1H), 3.39 (s, 3H),3.41 (s, 3H), 6.32 (br. s., 1H), 6.86-6.97 (m, 1H), 6.98-7.11 (m, 2H),7.16-7.29 (m, 2H), 7.52 (d, 1H), 8.59 (s, 1H), 12.47 (br. s, 1H).

Example 278 methyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate)

45 mg (0.09 mmol) of1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid from Example 277 were dissolved in 5 ml of methanol, 100 μl (1.31mmol) of thionyl chloride were added and the mixture was stirred atreflux temperature for 5 h. The reaction solution was concentrated underreduced pressure and the residue was dried under high vacuum. This gave46 mg (92% of theory) of the title compound.

LC/MS (Method 28): R_(t)=3.25 min; m/z=529 (M+H)⁺

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.70-1.90 (m, 1H), 2.07-2.19 (m, 2H),2.31-2.49 (m, 1H), 2.83-3.00 (m, 1H), 3.07 (d, 1H), 3.40 (s, 3H), 3.42(s, 3H), 3.82 (s, 3H), 6.27 (br. s., 1H), 6.91-6.99 (m, 1H), 7.00-7.11(m, 2H), 7.21 (d, 2H), 7.48 (t, 1H), 8.37 (s, 1H).

Example 279 methyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(enantiomer 1)

Enantiomer which elutes first (17 mg) from the separation of 45 mg ofthe racemic substance from Example 278 by means of preparative HPLC on achiral phase (Method 31).

Chiral analytical HPLC (Method 32): R_(t)=4.14 min, >99% ee.

LC/MS (Method 1): R_(t)=1.06 min; m/z=529 (M+H)⁺

Example 280 methyl1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(enantiomer 2)

Enantiomer which elutes last (19 mg) from the separation of 45 mg of theracemic substance from Example 278 by means of preparative HPLC on achiral phase (Method 31).

Chiral analytical HPLC (Method 32): R_(t)=4.68 min, 98% ee.

LC/MS (Method 1): R_(t)=1.06 min; m/z=529 (M+H)+

Example 2811-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (enantiomer 1)

14 mg (0.03 mmol) of the compound from Example 279 in 1.75 ml of glacialacetic acid/conc. hydrochloric acid 2:1 (v/v) were stirred at refluxtemperature for 2 h. The reaction mixture was concentrated under reducedpressure, and the residue was dissolved in acetonitrile and water andlyophilized. This gave 7 mg (48% of theory) of the title compound.

LC/MS (Method 1): R_(t): 1.10 min; m/z=515 (M+H)⁺

Example 2821-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (enantiomer 2)

16 mg (0.03 mmol) of the compound from Example 280 were stirred in 2 mlof a mixture of glacial acetic acid/conc. hydrochloric acid 2:1 (v/v) atreflux temperature for 2 h. The reaction mixture was concentrated underreduced pressure, and the residue was dissolved in acetonitrile andwater and lyophilized. This gave 13 mg (76% of theory) of the titlecompound.

LC/MS (Method 1): R_(t)=1.10 min; m/z=515 (M+H)⁺

Example 283 ethyl3-(5-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate)

400 mg (1.21 mmol) of ethyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 28A, 265 mg (1.45 mmol) of5-chloro-1,2,3,4-tetrahydronaphthalen-1-ol and 538 mg (2.05 mmol) oftriphenylphosphine were initially charged in 5 ml of THF and 10 ml ofDMF at RT. 391 mg (1.93 mmol) of DIAD were added and the reactionmixture was stirred at RT for 2 h. After adding a little 1M aqueoushydrochloric acid, the mixture was dissolved in DMSO and purified bymeans of preparative HPLC (Method 11). This gave 300 mg (47% of theory)of the title compound.

LC/MS (Method 1): R_(t)=1.13 min; m/z=496 (M+H)⁺

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.24 (t, 3H), 1.64-1.81 (m, 1H),1.93-2.11 (m, 2H), 2.21-2.42 (m, 1H), 2.51-2.71 (m, 1H), 2.94 (d, 1H),3.32 (s, 3H), 4.21 (q, 2H), 6.14 (br. s., 1H), 6.83 (d, 1H), 6.97 (t,2H), 7.13 (d, 3H), 8.22 (s, 1H).

Example 2843-(5-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (racemate)

270 mg (0.54 mmol) of ethyl3-(5-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 283 were stirred in 2 ml of conc. hydrochloric acid and 4ml of glacial acetic acid at reflux temperature. After cooling, themixture was purified by means of preparative HPLC (Method 15). This gave200 mg (79% of theory) of the title compound.

LC/MS (Method 1): R_(t=1.14) min; m/z=468 (M+H)⁺

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.73-1.90 (m, 1H), 2.03-2.23 (m, 2H),2.31-2.51 (m, 1H), 2.63-2.80 (m, 1H), 3.05 (d, 1H), 3.41 (s, 3H), 6.27(br. s., 1H), 6.89 (d, 1H), 7.08 (t, 2H), 7.14-7.29 (m, 3H), 8.56 (s,1H), 12.40 (br. s., 1H).

Example 285 methyl3-(5-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate)

50 mg (0.11 mmol) of the compound from Example 284 were dissolved in 5ml of methanol, and 117 μl (1.60 mmol) of thionyl chloride were added.The mixture was stirred at reflux temperature for 5 h, then concentratedon a rotary evaporator, and the residue was dried under high vacuum.This gave 51 mg (90% of theory) of the title compound.

LC/MS (Method 4): R_(t)=2.42 min; m/z=482 (M+H)⁺

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.80 (q, 1H), 2.01-2.21 (m, 2H),2.30-2.50 (m, 1H), 2.63-2.79 (m, 1H), 3.03 (d, 1H), 3.41 (s, 3H), 3.83(s, 3H), 6.06-6.41 (m, 1H), 6.91 (d, 1H), 7.03-7.11 (m, 2H), 7.14-7.26(m, 3H), 8.33 (s, 1H).

Example 286 methyl3-(5-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(enantiomer 1)

Enantiomer which elutes first from the separation of 152 mg of racemicmethyl3-(5-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(Example 285) by means of preparative HPLC on a chiral phase (Method29).

Chiral analytical HPLC (Method 30): R_(t)=4.44 min, >99% ee.

In order to remove solvent impurities, the resulting product waspurified by means of preparative HPLC (Method 15). This gave 34 mg ofthe title compound.

LC/MS (Method 1): R_(t)=1.08 min; m/z=482 (M+H)⁺

Example 287 methyl3-(5-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(enantiomer 2)

Enantiomer which elutes last from the separation of 152 mg of racemicmethyl3-(5-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(Example 285) by means of preparative HPLC on a chiral phase (Method29).

Chiral analytical HPLC (Method 30): R_(t)=5.87 min, 99% ee.

In order to remove solvent impurities, the resulting product waspurified by means of preparative HPLC (Method 15). This gave 27 mg ofthe title compound.

LC/MS (Method 1): R_(t)=1.08 min; m/z=482 (M+H)⁺

Example 2883-(5-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (enantiomer 1)

32 mg (66 mol) of the compound from Example 286 in 2 ml of glacialacetic acid/conc. hydrochloric acid 2:1 (v/v) were stirred at refluxtemperature for 2 h. The mixture was concentrated by rotary evaporation,dissolved in acetonitrile and water and lyophilized. This gave 33 mg(92% pure, 97% of theory) of the title compound.

LC/MS (Method 1): R_(t)=1.12 min; m/z=468 (M+H)⁺

Example 2893-(5-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (enantiomer 2)

25 mg (0.052 mmol) of the compound from Example 287 in 1.6 ml of glacialacetic acid/conc. hydrochloric acid 2:1 (v/v) were stirred at refluxtemperature for 2 h. The mixture was concentrated under reducedpressure, and the residue was dissolved in acetonitrile and water andlyophilized. This gave 24 mg (93% of theory) of the title compound.

LC/MS (Method 1): R_(t)=1.12 min; m/z=468 (M+H)⁺

Example 290 ethyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-3-[5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate)

217 mg (0.66 mmol) of ethyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(Example 28A), 170 mg (0.79 mmol) of5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ol and 292 mg (1.11mmol) of triphenylphosphine were initially charged in 3 ml of THF and 6ml of DMF at RT. 212 mg (1.05 mmol) of DIAD were added and the mixturewas stirred at RT for 2 h. After adding a little 1M aqueous hydrochloricacid, the mixture was dissolved in DMSO and purified by means ofpreparative HPLC (Method 15). This gave 114 mg (33% of theory) of thetitle compound.

LC/MS (Method 1): R_(t)=1.18 min; m/z=530 (M+H)⁺

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.24 (t, 3H), 1.65-1.80 (m, 1H),1.98-2.11 (m, 2H), 2.21-2.39 (d, 1H), 2.73-2.91 (d, 1H), 2.93-3.04 (m,1H), 3.32 (s, 3H), 4.22 (q, 2H), 6.19 (br. s., 1H), 6.97 (d, 1H),7.03-7.20 (m, 4H), 7.37-7.44 (m, 1H), 8.22 (s, 1H).

Example 2911-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-3-[5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (racemate)

95 mg (0.18 mmol) of the compound from Example 290 were stirred with 2ml of conc. hydrochloric acid and 4 ml of glacial acetic acid at refluxtemperature for 2 h. After cooling, the mixture was diluted with 5 ml ofacetonitrile and purified by means of preparative HPLC (Method 15). Thisgave 83 mg (92% of theory) of the title compound.

LC/MS (Method 1): R_(t)=1.15 min; m/z=502 (M+H)⁺

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.65-1.81 (m, 1H), 2.01-2.17 (m, 2H),2.25-2.39 (m, 1H), 2.76-2.92 (m, 1H), 2.96-3.10 (m, 1H), 3.33 (s, 3H),6.23 (br. s., 1H), 6.99 (d, 1H), 7.04-7.22 (m, 4H), 7.44 (d, 1H), 8.48(s, 1H), 12.30 (br. s, 1H).

Example 292 methyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-3-[5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate)

60 mg (0.12 mmol) of1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-3-[5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid from Example 291 were dissolved in 5 ml of methanol, and 131 μl(1.80 mmol) of thionyl chloride were added. The mixture was stirred atreflux temperature for 7 h, then concentrated on a rotary evaporator,and the residue was dried under high vacuum. This gave 60 mg (77% oftheory) of the title compound in 79% purity.

LC/MS (Method 28): R_(t)=3.40 min; m/z=516 (M+H)⁺

Example 293 methyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-3-[5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(enantiomer 1)

60 mg (0.12 mmol) of racemic methyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-3-[5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 292 were dissolved in 3 ml of acetonitrile and 1 ml ofethanol and separated on a Daicel Chiralpak IC column with 40%acetonitrile and 60% MTBE. Partial transesterification to the ethylester took place. As the fraction which eluted first, 14.5 mg of thetitle compound were obtained.

Chiral analytical HPLC (Method 30): R_(t)=3.99 min, 99% ee.

LC/MS (Method 1): R_(t)=1.11 min; m/z=516 (M+H)⁺

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.64-1.80 (m, 1H), 1.99-2.10 (m, 2H),2.23-2.36 (m, 1H), 2.75-2.90 (m, 1H), 2.94-3.04 (m, 1H), 3.32 (s, 3H),3.75 (s, 3H), 6.18 (br. s., 1H), 6.97 (d, 1H), 7.03-7.22 (m, 4H),7.37-7.45 (m, 1H), 8.25 (s, 1H).

As the fraction which eluted second, a mixture of the epimer of thetitle compound and the two enantiomers of the corresponding ethyl ester(43 mg) was obtained. This mixture was not purified any further.

Example 2941-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-3-[5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (enantiomer 1)

12 mg (0.02 mmol) of methyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-3-[5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 293 were stirred with 0.4 ml of a mixture of glacial aceticacid and conc. hydrochloric acid in a ratio of 2:1 at reflux temperaturefor 2 h. The mixture was concentrated, and the residue was dissolved inacetonitrile/water and then lyophilized. This gave 11 mg (91% of theory)of the title compound.

LC/MS (Method 1): R_(t)=1.12 min; m/z=502 (M+H)⁺

Example 295 ethyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-3-[5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate)

227 mg (0.66 mmol) of ethyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(Example 31A), 170 mg (0.79 mmol) of5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ol and 292.2 mg (1.11mmol) of triphenylphosphine were initially charged in 3 ml of THF and 6ml of DMF at RT. 206 μl (1.05 mmol) of DIAD were added and the reactionmixture was stirred at RT for 2 h. After adding a little 1M aqueoushydrochloric acid, the mixture was dissolved in DMSO and separated bymeans of preparative HPLC (Method 15). This gave 196 mg (52% of theory)of the title compound.

LC/MS (Method 1): R_(t)=1.23 min; m/z=546 (M+H)⁺

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.24 (t, 3H), 1.65-1.80 (m, 1H),1.99-2.11 (m, 2H), 2.23-2.38 (m, 1H), 2.75-2.90 (m, 1H), 2.94-3.05 (m,1H), 3.37 (s, 3H), 4.22 (q, 2H), 6.20 (br. s., 1H), 7.05 (d, 1H), 7.12(d, 2H), 7.15-7.28 (m, 1H), 7.29-7.46 (m, 2H), 8.23 (s, 1H).

Example 2961-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-3-[5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (racemate)

120 mg (0.21 mmol) of the compound from Example 295 in 2 ml of glacialacetic acid and 4 ml of conc. hydrochloric acid were stirred at refluxtemperature for 2 h. The reaction mixture was cooled, diluted with 5 mlof acetonitrile and purified by means of preparative HPLC (Method 15).This gave 85 mg (78% of theory) of the title compound.

LC/MS (Method 1): R_(t=1.18) min; m/z=518 (M+H)⁺

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.74-1.90 (m, 1H), 2.10-2.25 (m, 2H),2.40 (q, 1H), 2.83-2.99 (m, 1H), 3.05-3.15 (m, 1H), 3.46 (s, 3H), 6.32(br. s., 1H), 7.11-7.20 (m, 2H), 7.21-7.35 (m, 2H), 7.44 (br. s., 1H),7.52 (d, 1H), 8.57 (s, 1H), 12.38 (br. s, 1H).

Example 297 methyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-3-[5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate)

70 mg (0.14 mmol) of the compound from Example 296 were dissolved in 5ml of methanol, and 148 μl (2.03 mmol) of thionyl chloride were added.The mixture was stirred at reflux temperature for 7 h, then concentratedon a rotary evaporator, and the residue was dried under high vacuum.This gave 70 mg of the title compound in 75% purity (72% of theory).

LC/MS (Method 28): R_(t=3.59) min; m/z=532 (M+H)⁺

Example 298 methyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-3-[5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(enantiomer 1)

Enantiomer which elutes first (24 mg) from the separation of 70 mg ofthe racemic substance from Example 297 by means of preparative HPLC on achiral phase (Method 33).

Chiral analytical HPLC (Method 34): R_(t)=6.03 min, 99% ee.

LC/MS (Method 1): R_(t)=1.16 min; m/z=532 (M+H)⁺

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.72-1.88 (m, 1H), 2.05-2.20 (m, 2H),2.30-2.47 (m, 1H), 2.83-2.98 (m, 1H), 3.01-3.14 (m, 1H), 3.45 (s, 3H),3.83 (s, 3H), 6.18-6.37 (m, 1H), 7.05-7.37 (m, 4H), 7.48 (d, 2H), 8.34(s, 1H).

Example 299 methyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-3-[5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylateenantiomer 2)

Enantiomer which elutes last (29 mg) from the separation of 70 mg of theracemic substance from Example 297 by means of preparative HPLC on achiral phase (Method 33).

Chiral analytical HPLC (Method 34): R_(t)=7.37 min 99% ee

LC/MS (Method 1): R_(t)=1.16 min; m/z=532 (M+H)⁺

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.71-1.87 (m, 1H), 2.06-2.20 (m, 2H),2.30-2.46 (m, 1H), 2.82-2.99 (m, 1H), 3.01-3.12 (m, 1H), 3.45 (s, 3H),3.83 (s, 3H), 6.28 (br. s., 1H), 7.13 (d, 1H), 7.16-7.35 (m, 3H),7.38-7.57 (m, 2H), 8.34 (s, 1H).

Example 3001-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-3-[5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (enantiomer 1)

22 mg (0.04 mmol) of the compound from Example 298 were stirred with 2ml of glacial acetic acid/conc. hydrochloric acid in a ratio of 2:1(v/v) at reflux temperature for 2 h. The mixture was concentrated on arotary evaporator, and the residue was dissolved in acetonitrile/waterand then lyophilized. This gave 16 mg (75% of theory) of the titlecompound.

LC/MS (Method 1): R_(t)=1.16 min; m/z=518 (M+H)⁺

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.74-1.90 (m, 1H), 2.11-2.24 (m, 2H),2.31-2.46 (m, 1H), 2.84-3.00 (m, 1H), 3.04-3.15 (m, 1H), 3.46 (s, 3H),6.32 (br. s., 1H), 7.10-7.21 (m, 2H), 7.21-7.37 (m, 4H), 7.38-7.49 (m,1H), 7.52 (d, 1H), 8.58 (s, 1H), 12.38 (br.s, 1H).

Example 3011-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-3-[5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (enantiomer 2)

27 mg (0.05 mmol) of the compound from Example 299 in 2.5 ml of glacialacetic acid/conc. hydrochloric acid were stirred at reflux temperaturefor 2 h. The mixture was concentrated on a rotary evaporator and theresidue was dissolved in acetonitrile/water and lyophilized. This gave22 mg (81% of theory) of the title compound.

LC/MS (Method 1): R_(t)=1.19 min; m/z=518 (M+H)⁺

Example 302 ethyl3-(8-chloro-3,4-dihydro-1H-isochromen-4-yl)-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(racemate)

Under argon, 149.5 mg (0.45 mmol) of ethyl1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylatefrom Example 28A, 100.0 mg (0.54 mmol) of8-chloro-3,4-dihydro-1H-isochromen-4-ol (Example 120A) and 201.3 mg(0.77 mmol) of triphenylphosphine were dissolved in 4.8 ml of DMF and2.4 ml of THF. 146.0 mg (0.72 mmol) of DIAD were added dropwise and thereaction mixture was stirred at RT. After 2 h, 5 ml of aqueous 1Mhydrochloric acid were added and the mixture was separated by means ofpreparative HPLC (Method 15). This gave 59.0 mg (26% of theory) of thetitle compound.

LC/MS (Method 1): R_(t)=1.02 min; m/z=498 (M+H)⁺

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=1.31 (t, 3H), 3.41 (s, 3H), 4.08-4.15(m, 1H), 4.22-4.35 (m, 3H), 4.74 (d, 1H), 4.93 (d, 1H), 6.26-6.38 (m,1H), 7.00 (d, 1H), 7.03-7.08 (m, 1H), 7.13-7.26 (m, 4H), 8.31 (s, 1H).

Example 3033-(8-chloro-3,4-dihydro-1H-isochromen-4-yl)-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (racemate)

50 mg (0.10 mmol) of the compound from Example 302 were heated to refluxtemperature in 6.7 ml of a mixture of conc. hydrochloric acid/glacialacetic acid 1:2 for 50 min. After cooling to RT, the whole mixture wasseparated by means of preparative HPLC (Method 15). This gave 10 mg (21%of theory) of the title compound.

LC/MS (Method 1): R_(t)=0.98 min; m/z=470 (M+H)⁺

¹H NMR (400 MHz, CD₂Cl₂): δ [ppm]=3.41 (s, 3H), 4.17 (dd, 1H), 4.22-4.30(m, 1H), 4.76 (d, 1H), 4.94 (d, 1H), 6.28-6.40 (m, 1H), 6.99 (d, 1H),7.08 (d, 1H), 7.19 (t, 2H), 7.28 (d, 1H), 8.57 (s, 1H).

B. ASSESSMENT OF PHARMACOLOGICAL EFFICACY

The pharmacological action of the inventive compounds can be shown inthe assays described below:

Abbreviations:

Abz-HPFHL- 1-[N-(3- Lys(Dnp)-NH₂aminobenzoyl)histidylprolylphenylalanylhistidylleucyl-N⁶-(2,4-dinitrophenyl)lysine AMC 7-amido-4-methylcoumarin BNP brainnatriuretic peptide BSA bovine serum albumin CHAPS3-[(3-cholamidopropyl)dimethylammonio]-1- propanesulphonate HEPESN-(2-Hydroxyethyl)piperazine-N′-2-ethanesulphonic acid IC inhibitoryconcentration MeOSuc methoxysuccinyl NADP nicotinamide adeninedinucleotide phosphate PBS phosphate-buffered saline solution PEGpolyethylene glycol v/v volume to volume ratio (of a solution) w/vweight to volume ratio (of a solution)

B-1. Enzymatic Chymase Assay

The enzyme source used is recombinant human chymase (expressed in HEK293cells) or chymase purified from hamsters' tongues. The substrate usedfor chymase is Abz-HPFHL-Lys(Dnp)-NH₂. For the assay, 1 μl of a 50-foldconcentrated solution of test substance in DMSO, 24 μl of enzymesolution (dilution 1:80 000 human or 1:4000 hamster) and 25 μl ofsubstrate solution (final concentration 10 μM) in assay buffer (Tris 50mM (pH 7.5), sodium chloride 150 mM, BSA 0.10%, Chaps 0.10%, glutathione1 mM, EDTA 1 mM) were combined in a white 384-hole microtitre plate(Greiner Bio-One, Frickenhausen, Germany). The reaction is incubated at32 degrees for 60 min and the fluorescence emission at 465 nm afterexcitation at 340 nm is measured in a fluorescence reader, for exampleTecan Ultra (Tecan, Minnedorf, Switzerland).

One test compound is tested on the same microtitre plate in 10 differentconcentrations from 30 μM to 1 nM in a double determination. The dataare normalized (enzyme reaction without inhibitor=0% inhibition, allassay components without enzyme=100% inhibition) and IC₅₀ values arecalculated using in-house software. Compounds in the context of theinvention which were tested in this assay inhibited chymase activitywith an IC₅₀ of less than 10 μM.

IC₅₀ values representative of the inventive compounds are shown inTables 1 and 2 below:

TABLE 1 Hamster chymase Example No. IC 50 [nM] 1 8 2 7 3 9 4 64 5 20 833 9 1500 10 1600 13 5 14 10 15 330 16 14 18 10 20 8 21 5 22 6 25 7 27 528 4 33 4 34 7 35 6 37 700 40 15 41 23 42 7 43 643 44 18 45 50 47 35 4817 49 17 50 31 51 120 52 16 53 30 55 39 56 67 62 44 63 37 64 19 65 19 6630 67 4 75 82 76 41 77 170 78 140 79 210 81 65 82 83 220 86 140 89 84 9462 95 100 96 80 97 33 99 64 101 24 103 27 104 2 105 64 106 56 107 29 10876 109 24 110 150 111 20 112 113 6 114 7 115 10 116 20 117 3 118 6 119280 120 1025 121 3 122 2 123 4 124 7 125 6 126 10 127 34 128 7 129 450130 350 131 4 132 2 133 465 134 2 135 4 136 2 137 4 138 4 139 2 140 1141 2 142 1 143 2 144 2 145 2 146 1 147 2 148 4 149 2 150 5 151 2 152 19153 4 154 4 155 5 156 12 157 6 158 10 159 92 160 32 161 53 162 58 163 28164 34 165 40 166 62 167 91 168 49 169 370 170 20 171 17 172 27 173 110174 44 175 8 176 29 177 30 178 16 179 10 180 7 181 4 182 4 183 10 184170 185 140 186 23 187 4 188 4 189 3 190 140 191 16 192 5 193 8 194 13195 4 196 6 197 10 198 54 199 8 200 4 201 7 202 4 203 20 204 39 205 3206 3 207 4 209 13 211 20 213 18 214 20 215 26 216 183 217 1 218 4 219 5220 6 221 10 222 12 223 3 224 2 225 4 226 3 227 2 228 14 229 4 230 170231 21 232 6 233 470 234 270 235 9 236 5 238 45 239 490 240 67 241 2 24240 243 6 244 2 245 67 246 1 247 1 248 2 249 200 250 37 251 420 252 190253 1500 254 84 255 500 256 170 257 540 258 190 259 430 260 130 261 110262 2100 263 38 264 31 265 2 266 59 267 16 268 18

TABLE 2 Hamster chymase Example No. IC 50 [nM] 269 14 270 6 271 23 27211 273 1100 274 2 275 2300 276 4 277 2 278 5 279 4 280 250 281 1 282 88283 40 284 11 285 42 286 37 287 4500 288 14 289 970 290 8 291 4 292 29312 294 2 295 8 296 3 297 298 6 299 120 300 2 301 33 302 19 303 9

B-2. Measurement of Contraction on Isolated Aorta Rings from Hamsters

Male Syrian hamsters (120-150 g) were euthanized with carbon dioxide.The aorta was prepared and placed into ice-cold Krebs-Henseleit buffer.(Composition in mmol/1: sodium chloride 112, potassium chloride 5.9,calcium chloride 2.0, magnesium chloride 1.2, sodium dihydrogenphosphate1.2, sodium hydrogencarbonate 25, glucose 11.5). The aorta was cut intorings of length 2 mm, transferred to an organ bath filled with 5 ml ofKrebs-Henseleit buffer and connected to a myograph (DMT, Denmark). Thebuffer was warmed to 37° C. and sparged with 95% oxygen, 5% carbondioxide. In order to measure the isometric muscle contraction, the aortarings were mounted between two hooks. One of the hooks was connected toa pressure transducer. The second hook was movable and allowed precisesetting of the initial load by a protocol described by Mulvany andHalpem (Circulation Research 1977; 41:19-26).

Before each experiment, the responsiveness of the preparation was testedby adding potassium-containing Krebs-Henseleit solution (50 mmol/l KCl).A synthetic peptide, angiotensin 1-18, was used to induce contraction ofthe aorta rings. The angiotensin 1-18 is converted to angiotensin IIindependently of ACE. Subsequently, the aorta rings were incubated withthe test substance for 20 min and the contraction measurement wasrepeated. Chymase inhibition is shown as a reduction in the contractioninduced by angiotensin 1-18.

B-3. Isoprenaline-Induced Cardiac Fibrosis Model in Hamsters

For the experiments, male Syrian hamsters having a body weight of130-160 g were used. Cardiac hypertrophy and cardiac fibrosis wereinduced by a daily subcutaneous injection of 20 mg/kg isoprenaline over7 days. The test substance was administered orally to the animals 2hours before the injection of the isoprenaline. Control groups weretreated subcutaneously and orally with solvents in a correspondingmanner. At the end of the experiment, the hearts were removed, weighedand fixed. The fibrotic tissue on the histological sections from thehearts was marked with the aid of Sirius Red staining. Subsequently, thefibrotic area was determined by planimetry.

C. WORKING EXAMPLES OF PHARMACEUTICAL COMPOSITIONS

The inventive compounds can be converted to pharmaceutical formulationsas follows:

Tablet:

Composition:

100 mg of the inventive compound, 50 mg of lactose (monohydrate), 50 mgof corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF,Ludwigshafen, Germany) and 2 mg of magnesium stearate. Tablet weight 212mg, diameter 8 mm, radius of curvature 12 mm.

Production:

The mixture of inventive compound, lactose and starch is granulated witha 5% solution (m/m) of the PVP in water. After drying, the granules aremixed with the magnesium stearate for 5 minutes. This mixture is pressedwith a conventional tableting press (for tablet format see above). Theguide value used for the pressing is a pressing force of 15 kN.

Suspension for Oral Administration:

Composition:

1000 mg of the inventive compound, 1000 mg of ethanol (96%), 400 mg ofRhodigel® (xanthan gum from FMC, Pennsylvania, USA) and 99 g of water.

A single dose of 100 mg of the inventive compound corresponds to 10 mlof oral suspension.

Production:

The Rhodigel is suspended in ethanol; the inventive compound is added tothe suspension. The water is added while stirring. The mixture isstirred for approx. 6 h until swelling of the Rhodigel has ended.

Solution for Oral Administration:

Composition:

500 mg of the inventive compound, 2.5 g of polysorbate and 97 g ofpolyethylene glycol 400. A single dose of 100 mg of the inventivecompound corresponds to 20 g of oral solution.

Production:

The inventive compound is suspended in the mixture of polyethyleneglycol and polysorbate while stirring. The stirring operation iscontinued until dissolution of the inventive compound is complete.

I.V. Solution:

The inventive compound is dissolved in a concentration below thesaturation solubility in a physiologically acceptable solvent (e.g.isotonic sodium chloride solution, glucose solution 5% and/or PEG 400solution 30%). The solution is subjected to sterile filtration anddispensed into sterile and pyrogen-free injection vessels.

1. A compound of the formula (I)

in which R¹ is hydrogen or (C₁-C₄)-alkyl, R² is a group of the formula

where * is the attachment site to the uracil nitrogen atom, A is —CH₂—,—CH₂—CH₂—, —O—CH₂-## or oxygen, in which ## is the attachment site tothe phenyl ring, m is a number 0, 1 or 2, R⁴ is halogen, difluoromethyl,trifluoromethyl, (C₁-C₄)-alkyl, difluoromethoxy, trifluoromethoxy or(C₁-C₄)-alkoxy, R^(5A) is hydrogen or deuterium, R^(5B) is hydrogen,deuterium or (C₁-C₄)-alkyl, R⁶ is hydrogen or fluorine, R⁷ is hydrogenor fluorine, R⁸ is halogen, difluoromethyl, trifluoromethyl,(C₁-C₄)-alkyl or nitro, R⁹ is hydrogen, halogen, difluoromethyl,trifluoromethyl, (C₁-C₄)-alkyl, nitro or (C₁-C₄)-alkylthio, R³ is agroup of the formula

where # is the attachment site to the uracil nitrogen atom, the ring Qis 5- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl, inwhich 5- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl maybe substituted by 1 to 4 substituents independently selected from thegroup of halogen, difluoromethyl, trifluoromethyl, trideuteromethyl,(C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, oxo, hydroxyl, (C₁-C₄)-alkylcarbonyl,(C₁-C₄)-alkoxycarbonyl, aminocarbonyl and (C₁-C₄)-alkylsulphonyl, inwhich (C₁-C₆)-alkyl and (C₃-C₇)-cycloalkyl may in turn be substituted by1 to 3 substituents independently selected from the group of halogen,cyano, trifluoromethyl, (C₃-C₇)-cycloalkyl, hydroxyl, (C₁-C₄)-alkoxy and4- to 7-membered heterocyclyl,  and in which two (C₁-C6)-alkyl radicalsbonded to a carbon atom of 5- to 7-membered heterocyclyl and 5- or6-membered heteroaryl, together with the carbon atom to which they arebonded, may form a 3- to 6-membered carbocycle, R²⁴ is halogen,(C₁-C₄)-alkyl or (C₁-C₄)-alkoxy, n is a number 0, 1, 2 or 3, and thesalts, solvates and solvates of the salts thereof.
 2. The compound ofclaim 1 in which R¹ is hydrogen, methyl or ethyl, R² is a group of theformula

where * is the attachment site to the uracil nitrogen atom, A is —CH₂—,—CH₂—CH₂—, —O—CH₂-## or oxygen, in which ## is the attachment site tothe phenyl ring, R^(4A) is hydrogen, fluorine, chlorine, trifluoromethylor methyl, R^(4B) is hydrogen, fluorine, chlorine, trifluoromethyl ormethyl, with the proviso that at least one of the R^(4A) and R^(4B)radicals is not hydrogen, R^(5A) is hydrogen, R^(5B) is hydrogen, R⁶ ishydrogen, R⁷ is hydrogen, R⁸ is fluorine, chlorine, difluoromethyl,trifluoromethyl or methyl, R⁹ is fluorine, chlorine, difluoromethyl,trifluoromethyl or methyl, R³ is a group of the formula

where # is the attachment site to the uracil nitrogen atom, E is CR¹¹ orN, in which R¹¹ is hydrogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl oraminocarbonyl, E² is CR¹² or N, in which R¹² is hydrogen, (C₁-C₄)-alkylor (C₃-C₇)-cycloalkyl, E³ is NR¹⁴ or S, in which R¹⁴ is hydrogen,(C₁-C₄)-alkyl or (C₃-C₇)-cycloalkyl, G¹ is C═O or SO₂, G² isCR^(16A)R^(16B), NR¹⁷, O or S, in which R^(16A) is hydrogen, fluorine,(C₁-C₄)-alkyl or hydroxyl, R^(16B) is hydrogen, fluorine, chlorine,(C₁-C₄)-alkyl or trifluoromethyl, or R^(16A) and R^(16B) together withthe carbon atom to which they are bonded form a 3- to 6-memberedcarbocycle, R¹⁷ is hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl or(C₁-C₄)-alkoxycarbonyl, in which (C₁-C₆)-alkyl may be substituted by 1to 3 substituents independently selected from the group of fluorine,trifluoromethyl, cyano, (C₃-C₇)-cycloalkyl, hydroxyl, trifluoromethoxy,(C₁-C₄)-alkoxy, azetidinyl, oxetanyl, tetrahydrofuranyl andpyrrolidinyl, G³ is CR^(18A)R^(18B), NR¹⁹, O or S, in which R^(18A) ishydrogen, fluorine, (C₁-C₄)-alkyl or hydroxyl, R^(18B) is hydrogen,fluorine, chlorine, (C₁-C₄)-alkyl or trifluoromethyl, or R^(18A) andR^(18B) together with the carbon atom to which they are bonded form a 3-to 6-membered carbocycle, R¹⁹ is hydrogen, (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl or (C₁-C₄)-alkoxycarbonyl, in which (C₁-C₆)-alkyl maybe substituted by 1 to 3 substituents independently selected from thegroup of fluorine, trifluoromethyl, cyano, (C₃-C₇)-cycloalkyl, hydroxyl,trifluoromethoxy, (C₁-C₄)-alkoxy, azetidinyl, oxetanyl,tetrahydrofuranyl and pyrrolidinyl, G⁴ is CH₂, C═O or SO₂, K¹ is CH₂ orO, K² is CH₂ or O, with the proviso that only one of the K¹ and K²groups is O, D¹, D², D³ and D⁴ are each independently CR²³ or N, inwhich R²³ is hydrogen, halogen, (C₁-C₆)-alkyl or (C₃-C₇)-cycloalkyl,with the proviso that not more than 2 of the D¹, D², D³ and D⁴ groupsare N, R²⁴ is fluorine or methyl, n is a number 0 or 1, R¹⁰ is(C₁-C₄)-alkyl or (C₃-C₇)-cycloalkyl, in which (C₁-C₄)-alkyl may besubstituted by 1 or 2 substituents independently selected from the groupof fluorine, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxyl,methoxy, ethoxy, azetidinyl, oxetanyl, tetrahydrofuranyl andpyrrolidinyl, R¹³ is hydrogen, (C₁-C₄)-alkyl or (C₃-C₇)-cycloalkyl, R¹⁵is hydrogen, (C₁-C₆)-alkyl or (C₃-C₇)-cycloalkyl, in which (C₁-C₆)-alkylmay be substituted by 1 or 2 substituents independently selected fromthe group of fluorine, trifluoromethyl, cyclopropyl, cyclobutyl,hydroxyl, methoxy, ethoxy, azetidinyl, oxetanyl, tetrahydrofuranyl andpyrrolidinyl, R²⁰ is hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl or(C₁-C₄)-alkylcarbonyl, in which (C₁-C₆)-alkyl may be substituted by 1 or2 substituents independently selected from the group of fluorine,trifluoromethyl, cyclopropyl, cyclobutyl, hydroxyl, methoxy, ethoxy,azetidinyl, oxetanyl, tetrahydrofuranyl and pyrrolidinyl, R²¹ ishydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl or (C₁-C₄)-alkylsulphonyl,R^(22A) is hydrogen or (C₁-C₄)-alkyl, R^(22B) is hydrogen or(C₁-C₄)-alkyl, or R^(22A) and R^(22B) together with the carbon atom towhich they are bonded form a carbonyl group, and the salts, solvates andsolvates of the salts thereof.
 3. The compound of claim 1 in which R¹ ishydrogen, R² is a group of the formula

where * is the attachment site to the uracil nitrogen atom, A is —CH₂—,R^(4A) is chlorine or trifluoromethyl, R^(4B) is hydrogen, R³ is a groupof the formula

where # is the attachment site to the uracil nitrogen atom, E¹ is CR¹¹in which R¹¹ is hydrogen, E² is N, G¹ is C═O, G² is CR^(16A)R^(16B),NR¹⁷, O or S, in which R^(16A) is hydrogen, fluorine, methyl orhydroxyl, R^(16B) is hydrogen, fluorine, methyl or trifluoromethyl, orR^(16A) and R^(16B) together with the carbon atom to which they arebonded form a cyclopropyl ring, R¹⁷ is hydrogen, (C₁-C₄)-alkyl or(C₃-C₅)-cycloalkyl, in which (C₁-C₄)-alkyl may be substituted by 1 to 3substituents independently selected from the group of fluorine,trifluoromethyl, cyano, cyclopropyl, cyclobutyl, hydroxyl,trifluoromethoxy, methoxy, ethoxy, azetidinyl, oxetanyl,tetrahydrofuranyl and pyrrolidinyl, R²⁴ is hydrogen or fluorine, R¹⁰ is(C1-C4)-alkyl, R¹⁵ is hydrogen, methyl or ethyl, in which methyl andethyl may be substituted by 1 substituent selected from the group offluorine, trifluoromethyl and cyclopropyl, and the salts, solvates andsolvates of the salts thereof.
 4. The compound of claim 1 in which R¹ ishydrogen, R² is a group of the formula

where * is the attachment site to the uracil nitrogen atom, R^(5A) ishydrogen, R^(5B) is hydrogen, R⁶ is hydrogen, R⁷ is hydrogen, R⁸ isfluorine, chlorine or trifluoromethyl, R⁹ is fluorine, chlorine,trifluoromethyl or methyl, R³ is a group of the formula

where # is the attachment site to the uracil nitrogen atom, E¹ is CR¹¹in which R¹¹ is hydrogen, E² is N, G¹ is C═O, G² is CR^(16A)R^(16B),NR¹⁷, O or S, in which R^(16A) is hydrogen, fluorine, methyl orhydroxyl, R^(16B) is hydrogen, fluorine, methyl or trifluoromethyl, orR^(16A) and R^(16B) together with the carbon atom to which they arebonded form a cyclopropyl ring, R¹⁷ is hydrogen, (C₁-C₄)-alkyl or(C₃-C₅)-cycloalkyl, in which (C₁-C₄)-alkyl may be substituted by 1 to 3substituents independently selected from the group of fluorine,trifluoromethyl, cyano, cyclopropyl, cyclobutyl, hydroxyl,trifluoromethoxy, methoxy, ethoxy, azetidinyl, oxetanyl,tetrahydrofuranyl and pyrrolidinyl, R²⁴ is hydrogen or fluorine, R¹⁰ is(C₁-C₄)-alkyl, R¹⁵ is hydrogen, methyl or ethyl, in which methyl andethyl may be substituted by 1 substituent selected from the group offluorine, trifluoromethyl and cyclopropyl, and the salts, solvates andsolvates of the salts thereof.
 5. A process for preparing compounds ofthe formula (I) of claim 1, comprising: [A] reacting a compound of theformula (II)

in which R^(1A) is (C₁-C₄)-alkyl, T¹ is (C₁-C₄)-alkyl, T² is(C₁-C₄)-alkyl, in an inert solvent, optionally in the presence of asuitable base, with a compound of the formula (III)H₂N—R³  (III) in which R³ is as defined in claim 1 to give a compound ofthe formula (IV)

in which R^(1A) and R³ are each as defined above, reacting the compoundof formula (IV) in an inert solvent, in the presence of a suitable base,with a compound of the formula (V)X¹—R²  (V) in which R² is as defined in claim 1 and X¹ is hydroxyl or asuitable leaving group, especially chlorine, bromine or iodine to give acompound of the formula (I-1)

in which R^(1A), R² and R³ are each as defined above, or [B] convertinga compound of the formula (VI)

in which R^(1A) and T¹ are each as defined above, and T³ is(C₁-C₄)-alkyl in an inert solvent or else without solvent with acompound of the formula (III) to a compound of the formula (VII)

in which R^(1A), R³ and T³ are each as defined above, reacting thecompound of formula (VII) in an inert solvent with chlorosulphonylisocyanate to give a compound of the formula (IV) and converting thecompound of formula (IV) analogously to process [A] to a compound of theformula (I-1), or [C] reacting a compound of the formula (VIII)

in which R² is as defined in claim 1 in an inert solvent with a compoundof the formula (IX)

in which R^(1A) and T¹ are each as defined above and T⁵ is (C₁-C₄)-alkyland cyclized in the presence of a suitable base to give a compound ofthe formula (X)

in which R^(1A) and R² are each as defined above, reacting the compoundof formula (X) in an inert solvent, in the presence of a suitablecatalyst and a suitable base, with a compound of the formula (XI)

in which R³ is as defined above and T⁶ is hydrogen, (C₁-C₄)-alkyl, orthe two T⁶ radicals together form a —C(CH₃)₂—C(CH₃)₂— bridge to give acompound of the formula (I-1), or [D] hydrolysing a compound of theformula (I-1) in an inert solvent in the presence of a suitable acid orbase to give a compound of the formula (I-2)

in which R² and R³ are each as defined in claim 1 and R^(1B) ishydrogen, any protecting groups are detached and/or the compounds of theformulae (I-1) and (I-2) are, optionally, converted with the appropriate(i) solvents and/or (ii) bases or acids to the solvates, salts and/orsolvates of the salts thereof.
 6. (canceled)
 7. (canceled)
 8. Apharmaceutical composition comprising the compound of claim 1 one ormore inert nontoxic pharmaceutically suitable excipients.
 9. Thepharmaceutical composition of claim 8, at least one further activeingredients selected from the group consisting of a calcium antagonist,an angiotensin AII antagonist, an ACE inhibitor, a vasopeptidaseinhibitor, an endothelin antagonist, a renin inhibitor, analpha-receptor blocker, a beta-receptor blocker, a mineralocorticoidreceptor antagonist, a rho-kinase inhibitor, a diuretic, a kinaseinhibitor, a matrix metalloprotease inhibitor, a stimulator and/oractivator of soluble guanylate cyclase and a phosphodiesteraseinhibitor.
 10. (canceled)
 11. A method for treatment and/or prophylaxisof heart failure, pulmonary hypertension, chronic obstructive pulmonarydisease, asthma, kidney failure, nephropathy, fibrotic disorders of theinternal organs and dermatological fibroses comprising administering toa humans or and animals an effective amount of at least one compound ofclaim
 1. 12. A method for treatment and/or prophylaxis of heart failure,pulmonary hypertension, chronic obstructive pulmonary disease, asthma,kidney failure, nephropathy, fibrotic disorders of the internal organsand dermatological fibroses comprising administering to a human oranimal an effective amount of the pharmaceutical composition of claim 8.